Reconsideration of Chlorpyrifos: 2019 Toxicology Update
Reconsideration of chlorpyrifos Toxicology update JUNE 2019 © Australian Pesticides and Veterinary Medicines Authority 2019
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This publication is available from the APVMA website. CONTENTS iii
CONTENTS
EXECUTIVE SUMMARY 5
1 INTRODUCTION 7 Scope and objectives 7 Objective 1: Evaluation of the 2015–18 published mammalian studies on the putative low dose effects of chlorpyrifos 8 Literature search and triage strategy 8 In vivo thresholds for blood and brain cholinesterase inhibition 9 Hazard assessment of low dose chlorpyrifos exposure 13 Objective 2: To evaluate whether the 2015–18 published mammalian studies affects the validity of the current APVMA health based guidance values for chlorpyrifos 13 Objective 3: To re-evaluate Coulston et al Safety evaluation of DOWCO 179 in human volunteers. 1972 Dow AgroSciences Institute of Experimental Pathology and Toxicology, Albany Medical College, Albany, New York, USA 14 Posology, experimental design and evaluated endpoints 14 Results 15 Study quality 15 No observed effect level 16 Objective 4: To re-evaluate Kisicki, et al 1999 A rising dose toxicology study to determine the no- observable-effect-levels (NOEL) for erythrocyte acetylcholinesterase (AChE) inhibition and cholinergic signs and symptoms of chlorpyrifos at three dose levels. Dow Agrosciences, report No. DR#K-044793- 284 17 Posology, experimental design and evaluated endpoints 17 Results 18 Study quality 18 No observed effect level 19 Objective 5: To propose the new APVMA health based guidance values for chlorpyrifos based on all of the relevant, currently available information 20 Acceptable daily intake 20 Acute reference dose 22
2 CONCLUSIONS 23
3 REFERENCES 24
APPENDIX 1: LITERATURE SEARCH RESULTS 27
APPENDIX 2: STUDY ABSTRACTS AND STUDY EVALUATIONS 71
iv RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
LIST OF TABLES Table 1: Summary of online literature search strategy 8 Table 2: Toxicological thresholds for in vivo cholinesterase inhibition in mice 10 Table 3: Toxicological thresholds for peak cholinesterase inhibition in rats based on Marty et al (2012) and Reiss et al (2012) 11 Table 4: Toxicological thresholds for in vivo rat blood cholinesterase used in this evaluation 12 Table 5: Experimental design of Coulson et al (1972) 14 Table 6: Toxicological thresholds in other studies 20 EXECUTIVE SUMMARY 5
EXECUTIVE SUMMARY
The scope of this 2019 toxicology update was:
to evaluate the recent emergent published literature regarding the hypothesised adverse effects of low dose (doses below the threshold for inhibition of blood cholinesterases) chlorpyrifos treatment in vivo
to re-evaluate the regulatory studies suporting the current APVMA health based guidance values for chlorpyrifos
to propose new APVMA health based guidance values for chlorpyrifos.
The specific objectives of this update were:
to evaluate the recently published (2015–18) in vivo studies in laboratory mammals on the putative hazards of low dose exposure to chlorpyrifos
to evaluate whether the results of the recently published (2015–18) in vivo laboratory mammal studies affect the validity of the current APVMA health based guidance values for chlorpyrifos
to determine reliability and suitability of the human studies that support the current APVMA health based guidance values for chlorpyrifos
to determine if changes to the APVMA health based guidance values for chlorpyrifos were required.
Evaluation of the recently published (2015–18) in vivo mammalian studies on the putative hazards of low dose exposure to chlorpyrifos:
a systematic literature search covering the 2015–18 period identified a total of 500 published references. Using a literature triage strategy, 76 published studies were selected for detailed evaluation. No regulatory quality studies were identified. Overall, the putative effects of low dose chlorpyrifos (ie doses below the thresholds for inhibition of blood cholinesterases or ≤ 0.1 mg/kg bw/day in rats) remain poorly evaluated in human health-relevant in vivo animal models.
Evaluation of whether the recently published (2015–18) in vivo laboratory mammal studies affect the validity of the current APVMA health based guidance values for chlorpyrifos:
no new, regulatory quality data was identified
there is currently little regulatory quality in vivo experimental animal evidence that exposure to chlorpyrifos at doses below those that inhibit blood cholinesterases results in human health relevant adverse effects. Critically, the hypothesis that low doses of chlorpyrifos (ie doses below the thresholds for inhibition of blood cholinesterases or ≤ 0.1 mg/kg bw/day in rats) cause adverse developmental effects remains incompletely studied
however, there is now a substantial body of experimental evidence that exposure to chlorpyrifos at levels that result in detectable inhibition of blood cholinesterases (inhibition of butyryl- and/or acetylcholinesterase) may be a potentially serious neurodevelopmental and neurobehavioural developmental health hazard for humans. 6 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
Determine the reliability and suitability of the human studies that form the basis for the current APVMA health based guidance values for chlorpyrifos:
the single oral dose study in humans that forms the basis for the current APVMA acute reference dose for chlorpyrifos (0.1 mg/kg bw/day) is regarded as being appropriate, with limitations (low statistical power), for determination of APVMA’s acute reference dose for chlorpyrifos
the repeat daily oral dosing study in humans that forms the basis for the current APVMA acceptable daily intake for chlorpyrifos (0.003 mg/kg bw/day), while of appropriate quality for the era in which it was conducted, is no longer regarded as being compliant with modern regulatory expectations. Accordingly, it is no longer regarded as an appropriate basis for determination of the acceptable daily intake for chlorpyrifos.
Proposed new APVMA health based guidance values for chlorpyrifos:
the APVMA proposes to set a new acute reference dose based on the single oral dose no observed effect level for inhibition of erythrocyte cholinesterase in humans of 1 mg/kg bw. Because the acute reference dose is derived from humans, an interspecies uncertainty factor is not required. APVMA has retained the full ten-fold intraspecies uncertainty factor. APVMA has also applied an additional uncertainty factor of 100.5 to account for any additional uncertainties associated with the limitations of the underlying study. Accordingly the proposed new chlorpyrifos acute reference dose is 1/(10 x 100.5) ≈ 0.03 mg/kg bw
the APVMA proposes to set a new acceptable daily intake for chlorpyrifos based on the repeat oral dose no observed effect level for inhibition of blood cholinesterases (blood acetyl- and butyrylcholinesterases) in rats of 0.1 mg/kg bw/day. The proposed total intra- and interspecies uncertainty factors are 10 x 10 = 100. Accordingly the proposed new chlorpyrifos acceptable daily intake is 0.1/(10 x 10) = 0.001 mg/kg bw/day. INTRODUCTION 7
1 INTRODUCTION
Scope and objectives
The 2019 toxicology update was intended to supplement the published April 2017 reconsideration of chlorpyrifos: supplementary toxicology assessment report. The scope of this update was:
to evaluate the recent (2015–18) emergent published literature regarding the hypothesised adverse effects of low dose (doses below the threshold for inhibition of butyrylcholinesterase (plasma cholinesterase in humans, [EC 3.1.1.8]) and erythrocyte acetylcholinesterase [EC 3.1.1.7]) chlorpyrifos exposure in vivo. This evaluation is necessary because of the emerging hypothesis that the thresholds for inhibition of blood cholinesterases are inadequately protective surrogate biomarker points of departure for the establishment of human health based guidance values. The term ‘low dose chlorpyrifos’ within the context of this report is specifically defined as chlorpyrifos doses below the threshold doses for inhibition of blood cholinesterases
to re-evaluate the regulatory studies forming the basis of the current APVMA health based guidance values for chlorpyrifos
if indicated, to propose the new APVMA health based guidance values for chlorpyrifos.
The specific objectives of this report were as follows:
to evaluate the 2015–18 published in vivo mammalian studies on the putative hazards of low dose exposure to chlorpyrifos
to evaluate whether the 2015–18 published in vivo mammalian studies affects the validity of the current APVMA health based guidance values for chlorpyrifos
to re-evaluate Coulson and Goldberg 1972, Safety evaluation of DOWCO 179 in human volunteers, Institute of Experimental Pathology and Toxicology, Albany Medical College, Albany, New York, USA (Dow AgroSciences). This study is the basis for the current chlorpyrifos APVMA acceptable daily intake of 0.003 mg/kg bw/day
to re-evaluate Kisicki, J.C., Seip, C.W. & Combs, M.L. 1999, A rising dose toxicology study to determine the no-observable-effect-levels (NOEL) for erythrocyte acetylcholinesterase (AChE) inhibition and cholinergic signs and symptoms of chlorpyrifos at three dose levels, Report No. LLC Study ID: DR#K-044793-284 (Dow AgroSciences). This study is the basis for the current chlorpyrifos APVMA acute reference dose of 0.1 mg/kg bw
to propose the new APVMA health based guidance values for chlorpyrifos based on all of the relevant, currently available information. 8 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
Objective 1: Evaluation of the 2015–18 published mammalian studies on the putative low dose effects of chlorpyrifos
Literature search and triage strategy
The literature search strategy that was used to identify the published studies evaluated in this section is shown in Table 1.
Table 1: Summary of online literature search strategy
Tool Search characteristics
Combined search criteria (search field) Results
‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 39 references (date of addition in PubMed) AND ‘neuro*’ (all)
‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 274 references (date of addition in PubMed) AND ‘development’ (all)
‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 118 references (date of addition in PubMed) AND ‘behaviour’ (all)
‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 120 references (date of addition in PubMed) AND ‘rat’ (all)
‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 58 references (date of addition in PubMed) AND ‘mouse’ (all)
PubMed* ‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 6 references (date of addition in PubMed) AND ‘guinea pig’ (all)
‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 2 references (date of addition in PubMed) AND ‘dog’ (all)
‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 12 references (date of addition in PubMed) AND ‘human’ (all) AND ‘behaviour’
‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 34 references (date of addition in PubMed) AND ‘human’ (all) AND ‘development’
‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 11 references (date of addition in PubMed) AND ‘human’ (all) AND ‘neuro*’
‘Chlorpyrifos’ (all) AND ‘2015/01/01 to 2018/12/31’ 30 references (date of addition in PubMed) AND ‘human’ (all) AND ‘model*’
Total including duplicate/replicate references: 704 references INTRODUCTION 9
Tool Search characteristics
Combined search criteria (search field) Results
Total excluding duplicate/replicate references: 500 references
*PubMed; ncbi.nlm.nih.gov/pubmed
The complete list of identified published references is shown in Appendix 1.
The literature triage strategy applied to the references (identified in Appendix 1) was as follows:
non-mammalian studies were excluded since the objective was to evaluate the putative low dose effects of chlorpyrifos in laboratory mammals in vivo
in vitro studies were excluded since the objective was to evaluate the putative low dose effects of chlorpyrifos in vivo in laboratory mammals
studies on overt, high dose, acute chlorpyrifos cholinergic poisoning were excluded since the objective was to evaluate the putative low dose effects of chlorpyrifos. These papers provided no useful additional data for setting low dose human health based guidance values
studies that had inadequate dosimetry data or that inadequately described the doses used were excluded
studies that utilised multiple chemical co-exposures in the absence of a chlorpyrifos only treatment cohort were excluded
studies that were primarily ecotoxicological and/or ecochemical and/or bioremediative in nature were excluded
analytical method and other method development type studies were excluded
reviews that provided no additional new data were excluded.
The list of 76 studies that were identified for detailed evaluation following literature triage are shown in Appendix 2.
In vivo thresholds for blood and brain cholinesterase inhibition
Since the objective of this report was to determine if the 2015–18 published studies provide evidence for adverse effects following low dose chlorpyrifos exposure it was necessary to establish the thresholds for such effects in the evaluated species. The following sections examine the toxicological thresholds for chlorpyrifos effects on blood and brain cholinesterases in mice, rats and guinea pigs.
A common theme was identified throughout almost all of the rodent (rats, mice and guinea pig) studies evaluated: almost all of them deliberately selected chlorpyrifos doses (typically in the 1 to 6 mg/kg bw/day range for repeated dosing) that are known to produce adverse neurobehavioural effects in the absence of manifestly overt toxicity, ie study dose selections were designed not to result in deaths, overt clinical signs, overtly adverse pregnancy outcomes or overtly adverse effects on pup growth. Their objective was very specifically not to evaluate the low dose response relationships and/or dose thresholds of chlorpyrifos. Accordingly many of these of studies have limited value in terms of establishing human health based guidance values. However, these studies do recapitulate and reinforce earlier findings that exposure to chlorpyrifos at levels higher than those that inhibit blood cholinesterases (ie ‘high dose chlorpyrifos exposure’) results in adverse effects; particularly adverse effects on 10 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
neurodevelopment and neurobehavioural development. Thus these types of studies do have an important role in guiding public health policy regarding chlorpyrifos.
A second common theme was identified throughout almost all of the evaluated rodent studies: very few of them evaluated the interaction between dosing and time to peak blood and brain cholinesterase inhibition. Many of the studies that have made claims of an absence of detectable blood cholinesterase inhibition relied upon non- concurrent studies and non-concurrent control groups where measurements were not performed at the post- dosing peak inhibition time point (Marty et al 2012). Thus these studies may have erroneously underestimated the levels of blood and brain cholinesterase inhibition that were present in the experiments.
Mice
The thresholds for blood and brain cholinesterase in mice exposed to chlorpyrifos have been extensively evaluated by the FAO/WHO JMPR and APVMA (APVMA 2017, Wagner 1999; summarised in Table 2).
Table 2: Toxicological thresholds for in vivo cholinesterase inhibition in mice
Endpoint Exposure type Threshold type Value
Plasma cholinesterase Repeated LOEL 0.7 mg/kg bw/d inhibition
Erythrocyte cholinesterase Repeated NOEL 0.7 mg/kg bw/d inhibition
Brain cholinesterase Repeated NOEL 0.7 mg/kg bw/d inhibition
Based on Table 2, the blood cholinesterase inhibition threshold used for evaluation of repeated exposure studies in mice that has been used in this report is 0.7 mg/kg bw/d.
Rats
In a well-conducted series of regulatory quality studies, DOW (2010[a]) and Marty et al (2012) defined the oral exposure acute and repeated dose NOELs for chlorpyrifos-induced inhibition of blood cholinesterases in adult and pre-weaning age SD rats. The study of DOW (2010[b]) and Reis et al (2012) used the studies of Marty et al (2012) and DOW (2010[a]) to calculate the bench mark doses (BMD) and bench mark dose lows (BMDL; based on the lower 95 per cent confidence interval of the dose producing the bench mark response) for cholinesterase inhibition in rats. The dose thresholds derived from these studies are shown in Table 3. Notably, at low levels of chlorpyrifos exposure age had no consistent effect on the toxicological thresholds for cholinesterase inhibition over the pre- weaning to adult stages of development. The findings also demonstrated that the results of the benchmark dose (DOW 2010[b], Reis et al 2012) were broadly consistent (within a factor of ≤ 2-fold) with the NOELs derived from DOW (2010[a]) and Marty et al (2012). Both approaches also demonstrate that the thresholds for inhibition of blood cholinesterases were consistently lower (ie are potentially health-protective) than the threshold for inhibition of brain acetylcholinesterase. For the purposes of this report the lowest threshold for cholinesterases derived from DOW 2010[a], DOW 2010[b], Marty et al (2012) and Reis et al (2012) were used (Table 4). INTRODUCTION 11
Table 3: Toxicological thresholds for peak cholinesterase inhibition in rats based on Marty et al (2012) and Reiss et al (2012)
Benchmark dose
Duration of exposure Peak RBC AChE inhibition Peak brain AChE inhibition
BMD20 BMDL* BMD10 BMDL*
Acute dose (mg/kg bw) † 1.0 0.90 1.7 1.3
Repeat dose (mg/kg 0.21 0.19 0.67 0.53 bw/d)†
Age range No observed effect level Duration Vehicle n per over of dosing dose treatment Peak RBC AChE Peak plasma ChE Peak brain exposure method period days inhibition ֍ inhibition AChE† inhibition
Corn oil 8 ♂ 0.5 mg/kg bw ♂ 0.5 mg/kg bw ♂ 2.0 mg/kg bw Acute† PND 11 gavage sex/dose ♀ 0.5 mg/kg bw ♀ 0.5 mg/kg bw ♀ 2.0 mg/kg bw
8 ♂ 2.0 mg/kg bw ♂ 0.5 mg/kg bw ♂ 2.0 mg/kg bw Acute† Milk feeding PND 11 sex/dose ♀ 0.5 mg/kg bw ♀ 0.5 mg/kg bw ♀ 2.0 mg/kg bw
Corn oil 8 Acute† ≈ 70 ♀ 0.5 mg/kg bw ♀ 0.5 mg/kg bw ♀ 2.0 mg/kg bw gavage ♀/dose
Food 8 Acute† 12 h ≈ 70 ♀ 0.5 mg/kg bw ♀ 0.5 mg/kg bw ♀ 2.0 mg/kg bw ♀/dose feeding
♂ 0.1 mg/kg ♂ 0.5 mg/kg Repeated† Corn oil 8 bw/d ♂ 0.1 mg/kg bw/d bw/d PND 11 to 21 (11 days) gavage sex/dose ♀ 0.1 mg/kg ♀ 0.1 mg/kg bw/d ♀ 0.5 mg/kg bw/d bw/d
Repeated† Corn oil 8 ♀ 0.1 mg/kg ♀ 0.5 mg/kg ≈ 70–80 ♀ 0.1 mg/kg bw/d (11 days) gavage ♀/dose bw/d bw/d
Abbreviations: RBC = erythrocyte; AChE = acetylcholinesterase; ChE = cholinesterase; BMD = bench mark dose; BMDL = bench mark dose low; PND = post natal day(s) of age; mg = milligram; bw = body weight; d = day.
*Lower 95% confidence interval of the BMD.
† Measurements were at the time of peak cholinesterase inhibition as determined in a preliminary time -to-peak inhibition study. For PND 11 pups, the times-to-peak inhibition were 6 h post-dosing for chlorpyrifos in corn oil and 8 h post-dosing for chlorpyrifos in milk. For adult female rats, the times-to peak inhibition were 8 h post-dosing for chlorpyrifos in corn oil, and 8 h post-exposure for chlorpyrifos in diet. 12 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
֍ Note: butyrylcholinesterase (EC 3.1.1.8) is the predominant cholinesterase in human serum (> 99%), while in rats there is an approximately equal distribution of acetylcholinesterase (rat equivalent to EC 3.1.1.7) and butyrylcholinesterase (rat equivalent to EC 3.1.1.8) in plasma.
Table 4: Toxicological thresholds for in vivo rat blood cholinesterase used in this evaluation
Endpoint Threshold type Exposure type Value
Acute 0.5 mg/kg bw Plasma cholinesterase NOEL inhibition (all age ranges) Repeated 0.1 mg/kg bw/d
Acute 0.5 mg/kg bw Erythrocyte cholinesterase NOEL inhibition (all age ranges) Repeated 0.1 mg/kg bw/d
BMDL Acute 1 mg/kg bw/d* Brain cholinesterase inhibition (all age ranges) NOEL Repeated 0.5 mg/kg bw/d BMDL
*Rounded down
It should be noted that plasma cholinesterase determinations in rats are a composite measure of both acetyl (rat equivalent of EC 3.1.1.7) and butyrylcholinesterase (rat equivalent of EC 3.1.1.8) activities whereas human serum cholinesterase consists of > 99 per cent butyrylcholinesterase (Nolan 1997).
Further, it should be noted that in rats the relationships between blood cholinesterase activities, brain cholinesterase activities, and chlorpyrifos metabolism have a complex interaction during development (DOW 2010[a], Marty et al 2012). The maturation-associated changes in cholinesterase activities in blood and brain, when combined with the process of the maturation-associated changes in chlorpyrifos metabolism, results in a situation where the relative sensitivity of young vs adult rats to chlorpyrifos-induced cholinesterase inhibition is dose dependent. Young rats were not more sensitive than adults to chlorpyrifos—or chlorpyrifos oxon-induced cholinesterase inhibition over the lower portion of the chlorpyrifos dose response curve (doses < 2 mg/kg bw/d; DOW 2010[a], Marty et al 2012). However, at higher chlorpyrifos exposure levels (> 2 mg/kg bw/d), young rats became more sensitive than adults. APVMA regards the lower portion of the dose response curve (ie doses < 2 mg/kg bw/d) as being more directly relevant to the objective of establishing human health based guidance values for chlorpyrifos.
In terms of extrapolating rat data to humans, it is also important to note that central nervous system and blood brain barrier development in rats is altricial (ie rats are born somewhat less mature cf. humans; Adinolfi and Haddad 1977, Bonati et al 1981, Clancy et al 2007, Vidair 2004). Based on these characteristics, the full term human brain at birth is approximately equal to the rat brain at post-natal days 14 to 21 days of age (Bayer et al 1993). Thus findings in post-natal day 11 rats are not necessarily directly correlated with neurodevelopment in perinatal and neonatal humans. INTRODUCTION 13
Guinea pigs
The thresholds for inhibition of blood and brain cholinesterases have not been well established in this species. The relevant thresholds are assumed to be approximately the same as other rodents (ie about the same as rats and mice).
Hazard assessment of low dose chlorpyrifos exposure
The abstracts and evaluation of the 76 evaluated studies is shown in Appendix 2.
Mice
Of the 21 evaluated publications no reliable low dose chlorpyrifos studies were identified.
Rats
Of the 43 evaluated publications only three studies examined the effects of low dose chlorpyrifos treatment (Gómez-Giménez et al 2017 and 2018, Silva et al 2017). None of these studies were regarded as being of regulatory quality due to inadequacies of the statistical methods used, lack of blinding of the observer and/or other techniques to reduce observer bias, lack of assay validation by incorporation of appropriate control groups, lack of historical control data and insufficiently detailed short published study reports.
Guinea pigs
Of the three evaluated publications no reliable studies that utilised doses below the threshold for blood cholinesterases were identified. These studies provide no reliable evidence of low dose chlorpyrifos associated adverse effects and do not disprove the validity of using blood cholinesterases as health-protective biomarkers for human health risk assessment.
Humans
The small number of human studies evaluated in this report provide no additional information than what has already been evaluated in the APVMA 2017 supplementary toxicology report.
Objective 2: To evaluate whether the 2015–18 published mammalian studies affects the validity of the current APVMA health based guidance values for chlorpyrifos
Overall there was insufficient evidence in the evalulated 2015–18 published mammalian studies on chlorpyrifos that proves the hypothesis that thresholds for blood cholinesterase inhibition are inadequately protective points of departure for the derivation of human health based guidance values for the Australian population. However, the body of recent data did clearly demonstrate a systematic lack of regulatory quality data regarding putative low dose chlorpyrifos effects, particularly in the areas of neurological and neurobehavioural development. The dose response thresholds for such effects have not been adequately studied in vivo in human-relevant models. APVMA recognises and acknowledges the regulatory uncertainties created by these important data gaps. 14 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
Objective 3: To re-evaluate Coulston et al Safety evaluation of DOWCO 179 in human volunteers. 1972 Dow AgroSciences Institute of Experimental Pathology and Toxicology, Albany Medical College, Albany, New York, USA
This study evaluated the effects of administering technical grade chlorpyrifos (syn. DOWCO 179) to adult human males (basic demographic details not supplied) for up to 27 days (depending on dose). The central premise for limiting the duration of exposure to a maximum of 27 days was the lack of evidence of cumulative, chronic toxicological effects at the doses used. The separate statistical report (statistical analysis of data from report: Coulston, F., L. Golberg, and T. Griffen 1972, Safety Evaluation of DOWCO 179 in Human Volunteers, Institute of Experimental Pathology and Toxicology, Albany Medical College, Albany, New York (Dow AgroSciences)) was also reviewed.
Posology, experimental design and evaluated endpoints
Human subjects were assigned to four experimental groups. The study report did not state whether assignment to treatment group was randomised, if any attempts at cohort matching were made or if any other attempts at controlling potentially confounding variables and bias were made. It is assumed that no such procedures were incorporated in the study design. Importantly, the study does not appear to have been conducted using double blinding. Chlorpyrifos was administered in the form of an oral tablet (composition not stated) at the doses of 0 (placebo), 0.014, 0.03, 0.1 mg/kg bw/day with food (breakfast). The duration of treatment at the different doses and group sizes are summarised in Table 5.
Table 5: Experimental design of Coulson et al (1972)
Dose mg/kg bw/day Duration of treatment days Recovery period days* n
0 49 0 4 (Placebo)
0.014 27 0 4
0.03 20 6 4
0.1 9 18 4
*Twice weekly blood sample collection was continued until blood cholinesterase levels returned to pre-dosing levels.
Before administration of commencement of treatment, the clinical status of each volunteer was determined by means of a medical examination which included chest X-ray, electrocardiogram, urinalysis, and studies of haematology and serum chemistry. No baseline neurological or neurobehavioral evaluations were performed. There was insufficient information presented in the report regarding the criteria for admission to the study, including whether subjects not assessed to be clinically normal were excluded.
Following commencement of dosing, blood samples were collected twice each week for blood cholinesterase determination. Additional blood samples were collected weekly for haematology and clinical chemistry evaluations. Urine samples for evaluation were collected weekly for routine urinalysis and chemical analysis for chlorpyrifos INTRODUCTION 15
metabolites. There was insufficient information in the report to determine the frequency with which clinical signs were recorded. No neurological or neurobehavioural assessments were performed.
The statistical methods included curve-fitting procedures in which linear regressions were calculated for the response of each individual during the administration phase of the study. The slopes of the resulting regressions in each dosage group were averaged and the slope means were then submitted to a general analysis of variance.
Results
Termination of treatment
Cessation of treatment at 0.1 mg/kg bw/day appears to have occurred after dosing day nine due to detection of an approximate 64 per cent decrease in mean plasma cholinesterase activity cf. pre-dose baseline levels. Although not made clear in the report, inhibition of plasma cholinesterase may have been associated with the possible detection of muscarinic clinical signs and symptoms of anticholinesterase poisoning in one out of the four treatment subjects. However, insufficient information was provided to allow for a definitive conclusion. No rationale was given in the report for the timing of termination of treatment at lower doses.
Clinical signs
One in four subjects in the high dose group displayed signs and symptoms consistent with muscarinic anticholinesterase poisoning (runny nose, blurred vision, and a feeling of faintness) on day nine of treatment.
Haematology, clinical chemistry, erythrocyte cholinesterase determinations and urinalysis
No chlorpyrifos associated adverse effects were detected.
Plasma cholinesterase determinations
The plasma cholinesterase results through to treatment day 27 of the study are shown in Figure 1.
Study quality
The study, while possibly compliant with the standards in the era in which it was conducted, was not conducted in accordance with basic modern standards and study quality expectations. In particular:
it was not conducted in accordance with modern good clinical practice standards
it was not conducted in accordance with minimum current human clinical trial standards
the study report was short and lacking critical details based on modern expectations and standards
there were unexplained missing data
there were likely several unexplained protocol deviations
there was no quality assurance audit of the study
the study subjects were selected from a sub-population that is not representative of the broader human population (including putative sensitive sub-groups) 16 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
only one sex was evaluated
there was no blinding to treatment
there was no randomisation or cohort matching
the validity of the statistical methods is open to question
the reasons for the timing of cessation of dosing in some cohorts were not explicitly and clearly reported
there were no neurological/neurobehavioural assessments
the statistical power of the report (n = 4) was inadequate.
Overall the study is regarded as Klimisch score 3, ie not reliable. The study does supply some limited, low quality supportive data given that it was conducted in humans.
No observed effect level
Consistent with previous Australian evaluations of this study the NOEL for this study is 0.03 mg/kg bw/day based on a lack of significant (p > 0.05) inhibition of plasma cholinesterase at this dose. However the reliability of the NOEL was regarded as being of very low for the reasons stated above. The NOEL for this study is not sufficiently reliable as a point of departure for the determination of health based guidance values for chlorpyrifos. INTRODUCTION 17
8 Control 7 0.014 mg/kg bw/day 0.03 mg/kg bw/day 6 0.10 mg/kg bw/day
5
= = 4 n n
4
SD SD
3 Mean Mean
2
1 Plasma Cholinesterase Actibity Units/mL* Actibity Cholinesterase Plasma 0 Baseline 1Baseline 2 1 3 6 9 10 13 16 18 20 23 27 Day of Sampling (day)
Figure 1: Plasma cholinesterase. There was no significant (p < 0.05) differences betweent the control and 0.014 and 0.03 mg/kg bw/day cohorts. The plasma cholinesterase activity in the 0.03 mg/kg bw/day cohort was approximately 70 per cent of the pre-exposure baseline level and about 87 per cent of the control cohort when evaluated on a day to day basis (not significantly different cf. control; p > 0.05). The plasma cholinesterase activity in the 0.10 mg/kg bw/day cohort was significantly lower (p < 0.05) cf. the control group by study day nine (34 per cent of the baseline level in this cohort). Recovery of plasma cholinesterase activity in the 0.03 mg/kg bw/day cohort was completed within three weeks post-dosing. For the 0.1 mg/kg bw/day cohort, recovery was completed within four weeks.
Objective 4: To re-evaluate Kisicki, et al 1999 A rising dose toxicology study to determine the no-observable-effect-levels (NOEL) for erythrocyte acetylcholinesterase (AChE) inhibition and cholinergic signs and symptoms of chlorpyrifos at three dose levels. Dow Agrosciences, report No. DR#K-044793-284
Posology, experimental design and evaluated endpoints
The study design was a prospective, double-blinded, randomised, placebo controlled trial. Before being placed on study the volunteers were screened for general health according to set criteria and instructed to refrain from alcohol, strenuous exercise, and prescription medications before and during the study. The subjects were educated on the signs and symptoms of cholinergic toxicity and were instructed to inform the study physician of any adverse effects before the commencement of dosing.
Groups of six men and six women (per study phase) aged between 18 and 55 were administered a lactose powder capsule of chlorpyrifos at oral (overnight fasted) doses of 0, 0.5, 1 or 2 mg/kg bw. The study was conducted in two phases. During Phase I subjects were dosed at 0, 0.5, or 1 mg/kg bw. The subjects were then examined for possible chlorpyrifos associated effects. During Phase II subjects were dosed at either 0 or 2 mg/kg bw. 18 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
The subject’s vital signs (blood pressure, pulse, respiration, and temperature) were assessed before dosing and one, two, four, eight, 12, 24, 48, and 168 hours after treatment and the subjects were questioned regarding their well-being, symptoms and clinical signs at each sampling time point. During both study phases blood samples were collected 10 and 0 h before treatment and two, four, eight, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after treatment and analysed for erythrocyte cholinesterase activity and chlorpyrifos and its metabolites. Plasma cholinesterase levels were not measured. In addition, all urine voided from 48 hours before dosing to 168 hours after dosing was collected at 12 or six hour intervals and analysed for chlorpyrifos and metabolites. Electrocardiographic evaluations were performed. Haematology, clinical chemistry, urinalysis and an abbreviated physical examination were performed at study completion. General health parameters and clinical chemistry was checked at seven days post-dosing. Detailed neurological and neurobehavioural examinations were not performed.
Results
Protocol deviations and data gaps
There were no protocol deviations that were likely to have affected the outcome of the study. One male in the Phase 1 control cohort and one woman receiving 2 mg/kg bw did not provide a complete series of blood and urine samples.
Study completion
One woman withdrew from the study. This was associated with decreased erythrocyte cholinesterase activity. Although not stated in the report, it is possible that some clinical signs of anticholinesterase poisoning may have been present in this individual.
Symptoms, clinical signs, haematology, urinalysis and electrocardiogram
No chlorpyrifos-associated adverse effects were reported.
Erythrocyte cholinesterase levels
The only chlorpyrifos-associated effects that may have occurred were in the female subject dosed at 2 mg/kg bw who withdrew from the study. In this individual erythrocyte cholinesterase activities cf. pre-dose baseline values were 98.4 per cent of the pre-treatment value at four hours post-dosing, 77 per cent at eight hours post-dosing, 72 per cent at 12 hours post-dosing, 74 per cent at 24 hours post-dosing, 81 per cent at 36 hours post-dosing and 80 per cent at 48 hours post-dosing.
Study quality
The study was broadly consistent with minimum Phase I (initial investigational trial) and Phase II (exploratory trial) human clinical trial requirements at the time it was conducted. However, in terms of current modern Phase I INTRODUCTION 19
human clinical trial requirements, the study is non-compliant minimum expected requirements as per International Congress on Harmonisation (ICH) Efficacy Guidelines for the following reasons:1
the statistical evaluation was not consistent with modern ICH guideline requirements
low statistical power. The study had an n = 6 where n = minimum of 20 is currently more typically required in order to meet the minimum requirements of a Phase I trial as per ICH guideline E9. Notably, a minimum decrease in human erythrocyte cholinesterase of 17.3 per cent is needed to identify a statistical depression when there are two pre-exposure measurements (Gallo and Lawryk, 1991). On this basis, the study design was statistically underpowered. Furthermore, modern human clinical trial experience demonstrates that an n of 6 is insufficient for the evaluation of key safety and tolerability endpoints in humans
plasma cholinesterase levels were not measured
no pharmacokinetic evaluation was performed (non-compliant with ICH guidance document E8)
the study was not compliant with good clinical practice (ICH guidance document E6 (R2)). This includes insufficient reporting details regarding informed consent and lack of quality assurance.
Despite these limitations, it is important to note that the objective of the study was not to conduct a modern ICH compliant clinical pharmaceutical trial and the results of this study are meant to be interpreted within the context of the overall large body of regulatory quality data on chlorpyrifos (Wagner 1999). Accordingly, while APVMA recognises the scientific quality limitations of the study, the agency still regards Kisicki et al1999 as useful for setting of the acute reference dose for chlorpyrifos provided: (a) it is considered in conjunction with, and supported by, the available animal data; and (b) the uncertainties associated with the study outcome (particularly the study’s limited statistical power compared with modern minimum standards and the lack of neurological and neurobehavioural examinations) are taken into account. The study remains the best available acute exposure data in humans that is currently available to the agency.
No observed effect level
Consistent with previous evaluations of this study by WHO/FAO JMPR (Wagner 1999) the NOEL for this study was 1 mg/kg bw based on the absence of inhibition of erythrocyte cholinesterase. This finding is consistent with the lack of inhibition of blood cholinesterases in a published study where human volunteers were (low statistical power n = 5; no statistical analysis; regarded as unreliable) administered a single oral 1 mg/kg bw dose of chlorpyrifos (Griffin et al1999). Despite the uncertainties associated with Kisicki et al1999, its NOEL of 1 mg/kg bw is also broadly consistent (within a factor of two-fold) of the NOEL for acute inhibition of blood cholinesterases derived from reliable studies in rats (0.5 mg/kg bw; DOW 2010[a], Marty et al 2012,) which in turn, is more than two fold lower than the NOEL and BMDL for inhibition of brain cholinesterases in rats (≥ 1.3 mg/kg bw; Dow 2010[a], DOW 2010[b], Marty et al 2012, Reiss et al 2012).
1ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html 20 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
Objective 5: To propose the new APVMA health based guidance values for chlorpyrifos based on all of the relevant, currently available information
Acceptable daily intake
Point of departure
The APVMA no longer regards the current acceptable daily intake for chlorpyrifos of 0.003 mg/kg bw/day based on Coulston et al 1972 as reliable for regulatory purposes.
APVMA proposes establishing a new acceptable daily intake based on the recent series of studies in young and adult rats performed by DOW 2010[a] and Marty et al 2012. The NOEL for inhibition of blood cholinesterases (erythrocyte cholinesterase as well as plasma cholinesterases) for rats from post-natal day 11 of age to adulthood was 0.1 mg/kg bw/day (consistently five-fold lower than the threshold for inhibition of brain cholinesterases in this species). This point of departure is supported by the following toxicological thresholds in other studies that have been evaluated by the agency (Table 6).
Table 6: Toxicological thresholds in other studies
Reference Study type NOAEL Comments
13 week repeat 0.1 mg/kg bw/day Plasma and erythrocyte cholinesterase daily oral (dietary) based on inhibition of activities were decreased at doses ≥ 1 mg/kg Szabo et al 1988 dose toxicity study brain and erythrocyte bw/ day, and the activity of brain in F344 rats cholinesterases at acetylcholinesterase was decreased at 5 and higher doses 15 mg/kg bw/day
2 year repeat daily 0.1 mg/kg bw/day NOEL for inhibition of brain cholinesterase oral (dietary) based on inhibition of was 1 mg/kg bw/day based on consistent, Young and carcinogenicity erythrocyte and plasma statistically significant (p < 0.05) inhibition Grandjean 1988 study (OECD Test cholinesterases at at 10 mg/kg bw/day Guideline No. 451) higher doses in F344 rats
2 generation 0.1 mg/kg bw/d based NOAEL for inhibition of brain cholinesterase reporoductive on inhibition of blood and maternal toxicity was 1 mg/kg bw/day. toxicity study in SD cholinesterases at The NOAEL for developmental effects was Breslin et al 1991 rats higher doses 1 mg/kg bw/day, and the NOAEL for effects on fertility and reproductive effects was 5 mg/kg bw/day
Uncertainty factors
In order to account for any remaining uncertainties and for health-protective reasons, APVMA proposes applying the full ten-fold intra- and inter-species uncertainty factors as is consistent with established regulatory toxicology practice. Thus, the total uncertainty factor applied is 10 x 10 = 100.
Calculation of the proposed new acceptable daily intake
The proposed new acceptable daily intake is 0.1/(10 x 10) = 0.001 mg/kg bw/day (1 µg/kg bw/day). INTRODUCTION 21
Reliability of the proposed new acceptable daily intake
The reliability of the proposed new acceptable daily intake is regarded as being substantially lower than usual APVMA standards due to:
the very limited body of modern, systematic, regulatory quality data on the putative effects of low dose (ie doses ≤ 0.1 mg/kg bw/day) chlorpyrifos on complex neurobehavioural and neurobehavioural development in animal models
the results of the November 2016 US EPA Chlorpyrifos Revised Human Health Risk Assessment which indicated that the predicted human neurodevelopmental time weighted average (TWA) chlorpyrifos blood concentration LOAEL of 0.004 µg/L as the point of departure for derivation of human health based guidance values.2 This equates to points of departure for dietary exposure of between 0.12 to 0.2 µg/kg bw/day, ie five to ten-fold lower than the proposed new APVMA acceptable daily intake for chlorpyrifos. US EPA has indicated that a total uncertainty factor of 100-fold (ten-fold for intraspecies uncertainty and ten-fold for the Food Quality Protection Act factor) would be applied to the modelled chlorpyrifos blood concentration TWA LOAEL. APVMA notes that the physiologically based pharmacokinetic modelling (PBPK) approaches which are the basis of the 2016 US EPA evaluation, while likely reliable, are also dependent a single time point measurement of placental cord blood chlorpyrifos levels obtained as part of the Columbia Centre for Children’s Environmental Health studies on chlorpyrifos (evaluated in the APVMA 2017 supplementary toxicology report on chlorpyrifos). APVMA has three major remaining concerns regarding this approach adopted in the 2016 US EPA revised human health risk assessment:
no regulatory agency (including APVMA) has been able to independently evaluate the underlying Columbia Centre for Children’s Environmental Health data (despite numerous attempts by both US EPA and APVMA). A core principle of APVMA’s human health risk assessment approach is that the agency must be able to evaluate the quality and reliability of the key data that supports the derivation of human health based guidance values
the 2016 US EPA PBPK predicted human neurodevelopmental chlorpyrifos TWA blood concentration LOAEL of 0.004 µg/L has not been replicated in vivo in regulatory quality, human-relevant studies
a plausible mode of action for low dose chlorpyrifos effects (particularly at the 2016 US EPA TWA blood concentration LOAEL of 0.004 µg/L) on neuro- and neurodevelopment has not been fully experimentally established ie cause and effect based on the Bradford-Hill Criteria has not been fully established
the very limited body of modern, systematic, regulatory quality data on the putative effects of low dose (ie doses ≤ 0.1 mg/kg bw/day) chlorpyrifos on complex neurobehavioural and neurobehavioural development in animal models.
The most thorough approach to resolving APVMA’s concerns regarding the lower than usual reliability of the proposed new acceptable daily intake for chlorpyrifos is further regulatory quality testing regarding the putative low dose chlorpyrifos effects on neuro- and neuro-behavioural development. In particular, further dosimetry studies and low dose mode/mechanism of action data are required. APVMA also notes the critical need for independent evaluation and quality assurance assessment of relevant data generated by the Columbia Centre for Children’s Environmental Health studies on chlorpyrifos.
2regulations.gov/document?D=EPA-HQ-OPP-2015-0653-0454 22 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
Acute reference dose
Point of departure
APVMA has elected to retain the human acute, single dose NOEL for inhibition of plasma cholinesterase of 1 mg/kg bw derived from Kisicki et al 1999. This point of departure is supported by the NOEL of 0.5 mg/kg bw for inhibition of blood cholinesterases in rats (Marty et al 2012). Notably, US EPA has not set a specific acute food exposure human health based guidance value for chlorpyrifos in its 2016 revised human health risk assessment since this agency has concluded that their steady state dietary assessment is adequately protective of any acute food exposures.
Uncertainty factors
APVMA has elected to apply the full ten-fold intra-species uncertainty factor for calculating the acute reference dose. Since the point of departure was determined in humans, an inter-species uncertainty factor is not required. Because of the statistical power limitations (small n compared with modern human clinical trial standards) and other concerns associated with the Kisicki et al 1999 study (described above) APVMA is proposing to apply an additional uncertainty factor of 100.5-fold to account for any remaining uncertainties. The total uncertainty factor applied is thus 10 x 100.5.
Calculation of the proposed new acute reference dose
The proposed new acute reference dose is 1/(10 x 100.5) ≈ 0.03 mg/kg bw (30 µg/kg bw).
Reliability of the proposed new acute reference dose
With the addition of the additional uncertainty factor of 100.5 to account for any additional uncertainties associated with the Kisicki et al 1999 study the proposed new acute reference dose is regarded as being adequately health protective. Based on the currently available body of data there is little regulatory quality evidence that a single, acute, low dose exposure to chlorpyrifos at this level would result in adverse effects in humans (including susceptible sub-populations). However, APVMA notes that there is only a very limited body of modern, systematic, regulatory quality data on the putative acute effects of low dose (ie doses ≤ 0.1 mg/kg bw/day) chlorpyrifos on complex neurobehavioural and neurobehavioural development. CONCLUSIONS 23
2 CONCLUSIONS
The conclusions of the 2019 toxicology update are as follows:
there is currently little regulatory quality experimental in vivo evidence that exposure to chlorpyrifos at doses below those that inhibit blood cholinesterases results in human health relevant adverse effects. There is published, non-regulatory quality, modelling and epidemiological data that is suggestive of this
however, it is critical to note that the hypothesis that low doses of chlorpyrifos (ie doses below the thresholds for inhibition of blood cholinesterases or ≤ 0.1 mg/kg bw/day in rats) cause adverse developmental effects remains inadequately studied
there is now a very substantial body of experimental evidence that exposure to chlorpyrifos at levels that result in detectable inhibition of blood cholinesterases is a serious neurodevelopmental and neurobehavioural developmental health hazard for humans
APVMA proposes to establish a new acceptable daily intake of 0.001 mg/kg bw/day
APVMA proposes to establish a new acute reference dose of 0.03 mg/kg bw. 24 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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APPENDIX 1: LITERATURE SEARCH RESULTS
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10. Agatz A, Brown CD, Introducing the 2-DROPS model for two-dimensional simulation of crop roots and pesticide within the soil-root zone, Sci Total Environ, 2017 May 15; 586:966–75, doi: 10.1016/j.scitotenv.2017.02.076, Epub 2017 Feb 16, PubMed PMID: 28215806.
11. Agatz A, Schumann MM, French BW, Brown CD, Vidal S, Assessment of acute toxicity tests and rhizotron experiments to characterize lethal and sublethal control of soil-based pests, Pest Manag Sci, 2018 Nov; 74(11):2450–59, doi:10.1002/ps.4922, Epub 2018 May 17, PubMed PMID: 29575759.
12. Ahammed GJ, He BB, Qian XJ, Zhou YH, Shi K, Zhou J, Yu JQ, Xia XJ, 24-Epibrassinolide alleviates organic pollutants-retarded root elongation by promoting redox homeostasis and secondary metabolism in Cucumis 28 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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473. Yang Y, Kong W, Zhao L, Xiao Q, Liu H, Zhao X, Yang M, A multiresidue method for simultaneous determination of 44 organophosphorous pesticides in Pogostemon cablin and related products using modified QuEChERS sample preparation procedure and GC-FPD, J Chromatogr B Analyt Technol Biomed Life Sci, 2015 Jan 1; 974:118–25, doi: 10.1016/j.jchromb.2014.10.023, Epub 2014 Oct 25, PubMed PMID: 25463206.
474. Yang Y, Wang C, Xu H, Lu Z, Sublethal effects of four insecticides on folding and spinning behaviour in the rice leaffolder, Cnaphalocrocis medinalis (Guenée) (Lepidoptera: Pyralidae), Pest Manag Sci, 2018 Mar; 74(3):658–64, doi: 10.1002/ps.4753, Epub 2017 Dec 1, PubMed PMID: 28984412. 68 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
475. Yao J, Zhu YC, Adamczyk J, Luttrell R, Influences of acephate and mixtures with other commonly used pesticides on honey bee (Apis mellifera) survival and detoxification enzyme activities, Comp Biochem Physiol C Toxicol Pharmacol, 2018 Jul; 209:9–17, doi: 10.1016/j.cbpc.2018.03.005, Epub 2018 Mar 18, PubMed PMID: 29563044.
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477. Yazdinezhad A, Abbasian M, Hojjat Hosseini S, Naserzadeh P, Agh-Atabay AH, Hosseini MJ, Protective effects of Ziziphora tenuior extract against chlorpyrifos induced liver and lung toxicity in rat: Mechanistic approaches in subchronic study, Environ Toxicol, 2017 Sep; 32(9):2191–202, doi: 10.1002/tox.22432, Epub 2017 Jun 1, PubMed PMID: 28569040.
478. Ye YH, Li C, Yang J, Ma L, Xiao Y, Hu J, Rajput NA, Gao CF, Zhang YY, Wang MH, Construction of an immobilised acetylcholinesterase column and its application in screening insecticidal constituents from Magnolia officinalis, Pest Manag Sci, 2015 Apr; 71(4):607–15, doi: 10.1002/ps.3908, Epub 2014 Oct 20, PubMed PMID: 25228142.
479. Youssif BGM, Abdelrahman MH, Abdelazeem AH, Abdelgawad MA, Ibrahim HM, Salem OIA, Mohamed MFA, Treambleau L, Bukhari SNA, Design, synthesis, mechanistic and histopathological studies of small-molecules of novel indole-2-carboxamides and pyrazino[1,2-a]indol-1(2H)-ones as potential anticancer agents effecting the reactive oxygen species production, Eur J Med Chem, 2018 Feb 25; 146:260–73, doi: 10.1016/j.ejmech.2018.01.042, Epub 2018 Jan 31, PubMed PMID: 29407956.
480. Yu RX, Wang YH, Hu XQ, Wu SG, Cai LM, Zhao XP, Individual and Joint Acute Toxicities of Selected Insecticides Against Bombyx mori (Lepidoptera: Bombycidae), J Econ Entomol, 2016 Feb; 109(1):327–33, doi: 10.1093/jee/tov316, Epub 2015 Nov 6, PubMed PMID: 26546487.
481. Yuan H, Li G, Yang L, Yan X, Yang D, Development of melamine-formaldehyde resin microcapsules with low formaldehyde emission suited for seed treatment, Colloids Surf B Biointerfaces, 2015 Apr 1; 128:149–54, doi: 10.1016/j.colsurfb.2015.02.029, Epub 2015 Feb 23, PubMed PMID: 25734968.
482. Zainudin BH, Salleh S, Mohamed R, Yap KC, Muhamad H, Development, validation and determination of multiclass pesticide residues in cocoa beans using gas chromatography and liquid chromatography tandem mass spectrometry, Food Chem, 2015 Apr 1; 172:585–95, doi: 10.1016/j.foodchem.2014.09.123, Epub 2014 Sep 28, PubMed PMID: 25442595.
483. Zarei MH, Soodi M, Qasemian-Lemraski M, Jafarzadeh E, Taha MF, Study of the chlorpyrifos neurotoxicity using neural differentiation of acceptable daily intakepose tissue-derived stem cells, Environ Toxicol, 2016 Nov; 31(11):1510–9, doi: 10.1002/tox.22155, Epub 2015 May 27, PubMed PMID: 26018426.
484. Zhai C, Xu TF, Peng YK, Li YY, Detection of Chlorpyrifos on Spinach Based on Surface Enhanced Raman Spectroscopy with Silver Colloids, Guang Pu Xue Yu Guang Pu Fen Xi, 2016 Sep; 36(9):2835–40, Chinese, PubMed PMID: 30084609.
485. Zhang J, Dai H, Deng Y, Tian J, Zhang C, Hu Z, Bing G, Zhao L, Neonatal chlorpyrifos exposure induces loss of dopaminergic neurons in young adult rats, Toxicology, 2015 Oct 2; 336:17–25, doi: 10.1016/j.tox.2015.07.014, Epub 2015 Jul 26, PubMed PMID: 26215101. APPENDIX 1 69
486. Zhang LJ, Jing YP, Li XH, Li CW, Bourguet D, Wu G, Temperature-sensitive fitness cost of insecticide resistance in Chinese populations of the diamondback moth Plutella xylostella, Mol Ecol, 2015 Apr; 24(7):1611–27, doi: 10.1111/mec.13133, PubMed PMID: 25732547.
487. Zhang N, Liu J, Chen SN, Huang LH, Feng QL, Zheng SC, Expression profiles of glutathione S-transferase superfamily in Spodoptera litura tolerated to sublethal doses of chlorpyrifos, Insect Sci, 2016 Oct; 23(5):675– 87, doi: 10.1111/1744-7917.12202, Epub 2015 May 21, Erratum in: Insect Sci, 2016 Dec; 23 (6):924, PubMed PMID: 25641855.
488. Zhang R, Wu W, Zhang Z, Park Y, He L, Xing B, McClements DJ, Effect of the Composition and Structure of Excipient Emulsion on the Bioaccessibility of Pesticide Residue in Agricultural Products, J Agric Food Chem, 2017 Oct 18; 65(41):9128–38, doi: 10.1021/acs.jafc.7b02607, Epub 2017 Oct 4, PubMed PMID: 28914056.
489. Zhang X, Liao X, Mao K, Zhang K, Wan H, Li J, Insecticide resistance monitoring and correlation analysis of insecticides in field populations of the brown planthopper Nilaparvata lugens (stål) in China 2012–14, Pestic Biochem Physiol, 2016 Sep; 132:13–20, doi: 10.1016/j.pestbp.2015.10.003, Epub 2015 Oct 21, PubMed PMID: 27521908.
490. Zhang Y, Han Y, Yang Q, Wang L, He P, Liu Z, Li Z, Guo H, Fang J, Resistance to cycloxaprid in Laodelphax striatellus is associated with altered expression of nicotinic acetylcholine receptor subunits, Pest Manag Sci, 2018 Apr; 74(4):837–43, doi: 10.1002/ps.4757, Epub 2017 Dec 14, PubMed PMID: 28991400.
491. Zhang Y, Yang B, Li J, Liu M, Liu Z, Point mutations in acetylcholinesterase 1 associated with chlorpyrifos resistance in the brown planthopper, Nilaparvata lugens Stål, Insect Mol Biol, 2017 Aug; 26(4):453–60, doi: 10.1111/imb.12309, Epub 2017 Apr 13, PubMed PMID: 28407384.
492. Zhao J, Chen B, Species sensitivity distribution for chlorpyrifos to aquatic organisms: Model choice and sample size, Ecotoxicol Environ Saf, 2016 Mar; 125:161–9, doi: 10.1016/j.ecoenv.2015.11.039, Epub 2015 Dec 14, PubMed PMID: 26701839.
493. Zhao L, Xie F, Wang TT, Liu MY, Li JL, Shang L, Deng ZX, Zhao PX, Ma XM, Chlorpyrifos Induces the Expression of the Epstein-Barr Virus Lytic Cycle Activator BZLF-1 via Reactive Oxygen Species, Oxid Med Cell Longev, 2015; 2015:309125, doi: 10.1155/2015/309125, Epub 2015 Jul 14, PubMed PMID: 26257840; PubMed Central PMCID: PMC4516845.
494. Zhao Y, Zhang Y, Wang G, Han R, Xie X, Effects of chlorpyrifos on the gut microbiome and urine metabolome in mouse (Mus musculus), Chemosphere, 2016 Jun; 153:287–93, doi: 10.1016/j.chemosphere.2016.03.055, Epub 2016 Mar 26, PubMed PMID: 27018521.
495. Zhou XW, Zhao XH, Susceptibility of nine organophosphorus pesticides in skimmed milk towards inoculated lactic acid bacteria and yogurt starters, J Sci Food Agric, 2015 Jan; 95(2):260–6, doi: 10.1002/jsfa.6710, Epub 2014 May 21, PubMed PMID: 24777955.
496. Zhu J, Dubois A, Ge Y, Olson JA, Ren X, Application of human haploid cell genetic screening model in identifying the genes required for resistance to environmental toxicants: Chlorpyrifos as a case study, J Pharmacol Toxicol Methods, 2015 Nov-Dec; 76:76–82, doi: 10.1016/j.vascn.2015.08.154, Epub 2015 Aug 20, PubMed PMID: 26299976; PubMed Central PMCID: PMC4831576.
497. Zhu J, Li Y, Jiang H, Liu C, Lu W, Dai W, Xu J, Liu F, Selective toxicity of the mesoionic insecticide, triflumezopyrim, to rice planthoppers and beneficial arthropods, Ecotoxicology, 2018 May; 27(4):411–9, doi: 10.1007/s10646-018-1904-x, Epub 2018 Feb 5, PubMed PMID: 29404868. 70 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
498. Zuo YY, Huang JL, Wang J, Feng Y, Han TT, Wu YD, Yang YH, Knockout of a P-glycoprotein gene increases susceptibility to abamectin and emamectin benzoate in Spodoptera exigua, Insect Mol Biol, 2018 Feb; 27(1):36–45, doi:10.1111/imb.12338, Epub 2017 Jul 28, PubMed PMID: 28753233.
499. Zurlinden TJ, Reisfeld B, A Novel Method for the Development of Environmental Public Health Indicators and Benchmark Dose Estimation Using a Health-Based End Point for Chlorpyrifos, Environ Health Perspect, 2018 Apr 20; 126(4):047009, doi:10.1289/EHP1743, Erratum in: Environ Health Perspect, 2018 Sep; 126(9):99001, PubMed PMID: 29681141; PubMed Central PMCID: PMC6071752.
Zurlinden TJ, Reisfeld B, Erratum: A Novel Method for the Development of Environmental Public Health Indicators and Benchmark Dose Estimation Using a Health-Based Endpoint for Chlorpyrifos, Environ Health Perspect, 2018 Sep; 126(9):99001, doi: 10.1289/EHP4279, PubMed PMID: 30187771. APPENDIX 2 71
APPENDIX 2: STUDY ABSTRACTS AND STUDY EVALUATIONS
Summary Study and published abstract Study evaluation No.
1 Environ Toxicol Chem. 2018 Jul; 37(7):1898–906. doi: 10.1002/etc.4139. Epub 2018 May 7. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Comparative in vitro and in vivo effects of chlorpyrifos oxon in the outbred CD-1 mouse (Mus additional useful data on low dose chlorpyrifos effects. musculus) and great plains toad (anaxyrus cognatus). Anderson T, Liu J, McMurry S, Pope C. We compared biochemical, functional, and behavioural responses to the organophosphorus anticholinesterase chlorpyrifos oxon (CPO) in mice (mus musculus, CD-1) and toads (anaxyrus cognatus, Great Plains toad). Toads were substantially less sensitive to acute lethality of CPO based on the maximum tolerated (nonlethal) dose (toads, 77 mg/kg; mice, 5.9 mg/kg). Sublethal exposures led to classical signs of toxicity (increased involuntary movements, autonomic secretions) in mice but hypoactivity in toads. Motor performance in an inclined plane test was not affected by CPO in mice but was altered at the highest dosage in toads. Acetylcholinesterase (AChE), butyrylcholinesterase, monoacylglycerol lipase, and fatty acid amide hydrolase activities in brain were inhibited in mice but not in toads, and fatty acid amide hydrolase activity in the liver was inhibited in both species. Toad brain AChE was less sensitive to in vitro inhibition by CPO (50% inhibitory concentration [IC50; 20 min, 37 °C], 101 vs 7.8 nM; IC50 [20 min, 26 °C], 149 vs 6.2 nM), and studies of inhibitor kinetics indicated substantially lower anticholinesterase potency of CPO against the toad brain enzyme. Using an in vitro indirect inhibition assay, preincubation of CPO with toad brain homogenate was more effective than an equivalent mouse brain homogenate at reducing CPO potency. These data suggest that the relatively low sensitivity of toads to cholinergic toxicity is based on the low sensitivity of brain AChE, which in turn may be attributable to more effective target-site detoxification. Environ Toxicol Chem 2018; 37:1898-1906.
2 Food Chem Toxicol. 2018 Aug; 118:42–52. doi: 10.1016/j.fct.2018.04.065. Epub 2018 May 3. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Postnatal chlorpyrifos exposure and apolipoprotein E (APOE) genotype differentially affect additional useful data on low dose chlorpyrifos effects. cholinergic expression and developmental parameters in transgenic mice. Basaure P, Guardia-Escote L, Cabré M, Peris-Sampedro F, Sánchez-Santed F, Domingo JL, Colomina MT. 72 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
Summary Study and published abstract Study evaluation No.
Chlorpyrifos (CPF) is one of the most commonly used organophosphate pesticides in the world. Our previous results described that apolipoprotein E (APOE) polymorphisms are a source of individual differences in susceptibility to CPF. The aim of this study was to assess the physical and biochemical effects of postnatal exposure to CPF in the apoE targeted replacement mouse model. Mice were exposed to CPF at 0 or 1 mg/kg/day from postnatal day 10–15. Physical development, plasma and forebrain cholinesterase (ChE) activity and gene expression in liver and forebrain were evaluated. CPF exposure delays physical maturation and decreases the expression of choline acetyltransferase, α4-subunit and the α7 receptor. CPF decreases the expression of vesicular acetylcholine transporter (VAChT) mRNA in the forebrain only in apoE3 mice. The expression of paraoxonase-2 in the forebrain was also influenced by APOE genotype and CPF. Differences between genotypes were observed in litter size, ChE activity, expression of butyrylcholinesterase and paraoxonase-1 in liver and variants of acetylcholinesterase, VAChT and the α7 receptor in the forebrain. These results support that there are different vulnerabilities to postnatal CPF exposure according to the APOE polymorphism, which in turn affects the cholinergic system and defenses to oxidative stress.
3 Behav Brain Res. 2017 Feb 1; 318:1–11. doi: 10.1016/j.bbr.2016.10.014. Epub 2016 Oct 11. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Two cholinesterase inhibitors trigger dissimilar effects on behaviour and body weight in C57BL/6 additional useful data on low dose chlorpyrifos effects. mice: The case of chlorpyrifos and rivastigmine. Basaure P, Peris-Sampedro F, Cabré M, Reverte I, Colomina MT. Cholinesterases (ChE) are common targets of organophosphate (OP) pesticides and play a critical role in the pathology of some dementias. While chlorpyrifos (CPF) remains one of the most commonly used OPs in the world, numerous investigations have reported its neurotoxic potential and highlighted behavioural disturbances upon its administration. Rivastigmine currently serves to treat Alzheimer's disease, but it may induce cholinergic overstimulation in non-demented individuals. The present investigation aimed to compare the acute and delayed effects caused by both ChE inhibitors in adult C57BL/6 male mice. The animals were daily fed either a standard, a CPF- (5mg/kg body weight) or a rivastigmine-supplemented diet (1 or 2mg/kg body weight) for 8 weeks. After the treatment, we established an 8-week washout period to assess recovery. ChE enzyme activity, biomarkers, physical effects, and behavioural alterations were evaluated at APPENDIX 2 73
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different time points during the exposure and after the washout period. Both rivastigmine doses induced a time-dependent weight increase. CPF and rivastigmine inhibited brain acetylcholinesterase following an isoform-specific pattern. As for behavioural assessment, CPF negatively modulated learning strategies and impaired memory in a Barnes maze task at the end of the exposure. On the other hand, the low dose of rivastigmine improved memory recall at the end of the washout period in a Morris water maze. Indeed, our results endorse the positive effects of low doses of rivastigmine following a drug-free period in young mice. Therefore, doses and periodicity of treatment to improve cognition in elderly people upon rivastigmine administration should be revised.
4 J Environ Sci Health B. 2017 Feb; 52(2):77–83. doi: 10.1080/03601234.2016.1239973. Epub 2016 Chlorpyrifos dose used exceeds the in vivo NOAELs for Oct 24. cholinesterase inhibition in mice. The study provides no additional useful data on low dose chlorpyrifos effects. Mother gestational exposure to organophosphorus pesticide induces neuron and glia loss in daughter adult brain. Chen XP, Chao YS, Chen WZ, Dong JY. Chlorpyrifos (CPF) is a widely used organophosphorus pesticide with developmental neurotoxicity such as morphogenesis toxicity. In the present study, we assessed the effects of prenatal CPF exposure on systemic parameters and cytoarchitecture of medial prefrontal cortex (mPFC) in adulthood. Gestational dams were exposed to 5mg/kg/d of CPF during gestational days 13–17, while body weight, organ coefficient, and neuron and glia counts of offspring were determined on postnatal day 60. Our results showed that CPF treatment induced little or no effects on body weight and organ coefficients. There were also no significant pathological changes in mPFC. However, neuron and glia count analysis showed that CPF treatment reduced neuron and glia counts in anterior cingulate, prelimbic, and infralimbic areas of mPFC. The CPF react pattern was similar in both sexes, and there was no statistical difference in most of the sub-regions. Thus, our results revealed an embryonic origin brain deficit induced by gestational mother pesticide exposure.
5 Toxicol Res (Camb). 2016 Jun 14; 5(5):1359–70. doi: 10.1039/c5tx00282f. eCollection 2016 Sep 1. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no An in vivo study in mice: mother's gestational exposure to organophosphorus pesticide retards the additional useful data on low dose chlorpyrifos effects. division and migration process of neural progenitors in the fetal developing brain. 74 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
Summary Study and published abstract Study evaluation No.
Chen XP, Wang TT, Wu XZ, Wang DW, Chao YS. Background: Widely utilized pesticides such as chlorpyrifos (CPF) can cause cognitive abnormalities, neurotransmitter disruptions and brain cytoarchitecture deficits in adulthood due to exposure in the prenatal period, but the mechanism underlying the development and maintenance of such neurotoxicity in embryonic neurogenesis remains largely unclear. Using embryonic neocortex slices, we investigated mitosis population constituents and characteristic interkinetic nuclear migration (INM) to evaluate the CPF effects on the proliferation process of neural progenitors. Methods: Gestational days (GD) 14 and GD 7.5–11.5 ICR dams were exposed to 5 mg kg–1 of CPF to investigate immediate toxicity and sustained toxicity. Proliferating nuclei were labeled with 50 mg kg-1 of Brdu at 1, 3, 6 and 9 hours before samples were collected. The mitoses count and Brdu positive nuclei (BPN) location were measured and analyzed in standard sections of the embryonic dorsolateral cortex. Results: CPF reduced the mitoses count in the primary progenitors but not in the secondary progenitors which are time sustained. CPF retarded BPN migration with a 6–9 μm delay of the relative location in the immediate groups and a 3–6 μm delay in the sustained ones. CPF had no or little effects on the global mitoses count and BPN count. Conclusion: Prenatal CPF exposure disrupts the proliferation process of primary progenitors in the embryonic dorsolateral cortex immediately and with sustained effects, which may contribute to explain the toxicity mechanism in early neurogenesis.
6 J Neuroinflammation. 2016 Jun 14; 13(1):149. doi: 10.1186/s12974-016-0617-4. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress additional useful data on low dose chlorpyrifos effects. and prostaglandin E2 synthesis in a mouse model of idiopathic autism. The dose (6 mg/kg bw/d) was selected on the basis of De Felice A, Greco A, Calamandrei G, Minghetti L. previous multidose studies because it was effective at BACKGROUND: Autism spectrum disorders (ASD) are emerging as polygenic and multifactorial producing behavioural changes in the absence of overt toxic disorders in which complex interactions between defective genes and early exposure to symptoms in dams or major effects on pregnancy length, environmental stressors impact on the correct neurodevelopment and brain processes. number of pups at delivery, sex ratio, pups weight at delivery Organophosphate insecticides, among which chlorpyrifos (CPF), are widely diffused environmental and growing rate. toxicants associated with neurobehavioural deficits and increased risk of ASD occurrence in children. Oxidative stress and dysregulated immune responses are implicated in both organophosphate neurodevelopmental effects and ASD etiopathogenesis. BTBR T+tf/J mice, a well- studied model of idiopathic autism, show several behavioural and immunological alterations found in APPENDIX 2 75
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ASD children, and we recently showed that CPF gestational exposure strengthened some of these autistic-like traits. In the present study, we aimed at investigating whether the behavioural effects of gestational CPF administration are associated with brain increased oxidative stress and altered lipid mediator profile. METHODS: Brain levels of F2-isoprostanes (15-F2t-IsoP), as index of in vivo oxidative stress, and prostaglandin E2 (PGE2), a major arachidonic acid metabolite released by immune cells and by specific glutamatergic neuron populations mainly in cortex and hippocampus, were assessed by specific enzyme-immuno assays in brain homogenates from BTBR T+tf/J and C57Bl6/J mice, exposed during gestation to either vehicle or CPF. Measures were performed in mice of both sexes, at different postnatal stages (PNDs 1, 21, and 70). RESULTS: At birth, BTBR T+tf/J mice exhibited higher baseline 15-F2t-IsoP levels as compared to C57Bl6/J mice, suggestive of greater oxidative stress processes. Gestational treatment with CPF-enhanced 15-F2t-IsoP and PGE2 levels in strain-and age- dependent manner, with 15-F2t-IsoP increased in BTBR T+tf/J mice at PNDs 1 and 21, and PGE2 elevated in BTBR T+tf/J mice at PNDs 21 and 70. At PND 21, CPF effects were sex-dependent being the increase of the two metabolites mainly associated with male mice. CPF treatment also induced a reduction of somatic growth, which reached statistical significance at PND 21. CONCLUSIONS: These findings indicate that the autistic-like BTBR T+tf/J strain is highly vulnerable to environmental stressors during gestational period. The results further support the hypothesis that oxidative stress might be the link between environmental neurotoxicants such as CPF and ASD. The increased levels of oxidative stress during early postnatal life could result in delayed and long- lasting alterations in specific pathways relevant to ASD, of which PGE2 signaling represents an important one.
7 PLoS One. 2015 Mar 24; 10(3):e0121663. doi: 10.1371/journal.pone.0121663. eCollection 2015. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Prenatal exposure to a common organophosphate insecticide delays motor development in a mouse additional useful data on low dose chlorpyrifos effects. model of idiopathic autism. The dose (6 mg/kg bw/d) was selected on the basis of De Felice A, Scattoni ML, Ricceri L, Calamandrei G. previous multidose studies because it was effective at Autism spectrum disorders are characterized by impaired social and communicative skills and producing behavioural changes in the absence of overt toxic repetitive behaviours. Emerging evidence supported the hypothesis that these neurodevelopmental symptoms in dams or major effects on pregnancy length, disorders may result from a combination of genetic susceptibility and exposure to environmental number of pups at delivery, sex ratio, pups weight at delivery toxins in early developmental phases. This study assessed the effects of prenatal exposure to and growing rate. chlorpyrifos (CPF), a widely diffused organophosphate insecticide endowed with developmental 76 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
Summary Study and published abstract Study evaluation No.
neurotoxicity at sub-toxic doses, in the BTBR T+tf/J mouse strain, a validated model of idiopathic autism that displays several behavioural traits relevant to the autism spectrum. To this aim, pregnant BTBR mice were administered from gestational day 14 to 17 with either vehicle or CPF at a dose of 6 mg/kg/bw by oral gavages. Offspring of both sexes underwent assessment of early developmental milestones, including somatic growth, motor behaviour and ultrasound vocalization. To evaluate the potential long-term effects of CPF, two different social behaviour patterns typically altered in the BTBR strain (free social interaction with a same-sex companion in females, or interaction with a sexually receptive female in males) were also examined in the two sexes at adulthood. Our findings indicate significant effects of CPF on somatic growth and neonatal motor patterns. CPF treated pups showed reduced weight gain, delayed motor maturation (ie, persistency of immature patterns such as pivoting at the expenses of coordinated locomotion) and a trend to enhanced ultrasound vocalization. At adulthood, CPF associated alterations were found in males only: the altered pattern of investigation of a sexual partner, previously described in BTBR mice, was enhanced in CPF males, and associated to increased ultrasonic vocalization rate. These findings strengthen the need of future studies to evaluate the role of environmental chemicals in the etiology of neurodevelopment disorders.
8 Pestic Biochem Physiol. 2018 Jan; 144:36–41. doi: 10.1016/j.pestbp.2017.11.002. Epub 2017 Nov Study used chlorpyrifos-ethyl and provides no additional 10. useful data on low dose chlorpyrifos neurological effects. Chlorpyrifos-induced parkinsonian model in mice: Behaviour, histopathology and biochemistry. Deveci HA, Karapehlivan M. INTRODUCTION: The aim of this study was to investigate the protective effect of caffeic acid phenethyl ester (CAPE) on Paraoxonase (PON1) activity, and levels of lipid profile, total sialic acid (TSA), total antioxidant capacity (TAC) and total oxidant capacity (TOC) in the plasma and brain tissue of mice with chlorpyrifos-ethyl (CPF)-induced Parkinson. MATERIAL AND METHOD: In the study, 35 male Swiss albino mice were divided into 5 groups including equal number of mice as follows; intraperitoneal injection of saline for mice in control (C) group, subcutaneous injection of 80mg/kg CPF for CPF group, intraperitoneal injection of 10μmol/kg CAPE for CAPE group, subcutaneous injection of 80mg/kg CPF and intraperitoneal injection of 10μmol/kg CAPE for CPF+CAPE group and intraperitoneal injection of 10% ethanol diluted in physiological saline solution for 21days for ethanol (E) group. All the mice were fed with normal feed and tap water ad libitum. At the end of the study, PON1 activity, lipid profile (except for brain), and TSA, TAC and APPENDIX 2 77
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TOC levels in the plasma and brain tissue were analyzed. Tissue samples of brain substantia nigra were evaluated histopathologically. RESULTS: Levels of plasma TAC, high density lipoprotein (HDL) and PON1 activity were statistically lower in CPF group than the other groups (P<0.001). Also, levels of plasma TOC, TSA, total cholesterol, triglycerides, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) were statistically higher in CPF group than the other groups(P<0.001). PON1 activity and level of TAC were significantly lower in brain tissue of CPF groups (P<0.001). In addition, TOC and TSA levels were significantly higher in brain tissue in CPF group (P<0.001). CONCLUSION: In conclusion, CAPE showed a protective effect on PON1 activity and levels of lipid profile, TSA, TAC and TOC in plasma and brain tissue and prevented the neurodegenerations in brain tissue in CPF-induced Parkinson's disease.
9 Food Chem Toxicol. 2018 Dec; 122:1–10. doi: 10.1016/j.fct.2018.09.069. Epub 2018 Sep 29. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Postnatal exposure to chlorpyrifos produces long-term effects on spatial memory and the cholinergic additional useful data on low dose chlorpyrifos effects. system in mice in a sex- and APOE genotype-dependent manner. Guardia-Escote L, Basaure P, Blanco J, Cabré M, Pérez-Fernández C, Sánchez-Santed F, Domingo JL, Colomina MT. Organophosphorus pesticides—and in particular chlorpyrifos (CPF)—are extensively used worldwide. They mainly exert their toxicity by targeting the cholinergic system. Several studies suggested that the gene coding for apolipoprotein E (apoE), which is a risk factor for several diseases, can also confer different vulnerability to toxic insults. This study was aimed at assessing the long-term effects of postnatal exposure to CPF on learning and memory as well as the expression levels of several genes involved in cholinergic neurotransmission in mice. Both male and female apoE4-TR and C57BL/6 mice were exposed to either 0 or 1 mg/kg/day of CPF by oral gavage using a micropipette on postnatal days 10–15. At 9 months, they were tested in a Morris Water Maze (MWM) and the gene expression in the frontal cortex and hippocampus was evaluated. Our results show that, in males, CPF had an effect on the spatial retention, while in females, it altered the expression levels of nicotinic receptors. Furthermore, apoE4-TR mice performed the worst during the MWM retention and presented low expression levels in a considerable number of cholinergic genes. Taken together, the current results reveal long-term effects in mice nine months after postnatal exposure to CPF, which are modulated by sex and apoE4 genotype. 78 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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10 Food Chem Toxicol. 2018 Aug; 118:821–9. doi: 10.1016/j.fct.2018.06.051. Epub 2018 Jun 21. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Inhibition of cholinergic and non-cholinergic targets following subacute exposure to chlorpyrifos in additional useful data on low dose chlorpyrifos effects. normal and high fat fed male C57BL/6J mice. Howell GE 3rd, Kondakala S, Holdridge J, Lee JH, Ross MK. The effects of obesity on organophosphate pesticide-mediated toxicities, including both cholinergic and non-cholinergic targets, have not been fully elucidated. Therefore, the present study was designed to determine if high fat diet intake alters the effects of repeated exposure to chlorpyrifos (CPS) on the activities of both cholinergic and noncholinergic serine hydrolase targets. Male C57BL/6J mice were placed on either standard rodent chow or high fat diet for four weeks with CPS exposure (2.0 mg/kg) for the last 10 days of diet intake. Exposure to CPS did not alter acetylcholinesterase in the central nervous system, but it did significantly inhibit circulating cholinesterase activities in both diet groups. CPS significantly inhibited hepatic carboxylesterase and fatty acid amide hydrolase and this inhibition was significantly greater in high fat fed animals. Additionally, CPS exposure and high fat diet intake downregulated genes involved in hepatic de novo lipogenesis as well as cytochrome P450 enzymes involved in hepatic xenobiotic metabolism. In summary, the present study demonstrates that high fat diet intake potentiates CPS mediated inhibition of both carboxylesterase and fatty acid amide hydrolase in the liver of obese animals following subacute exposure and suggests obesity may be a risk factor for increased non- cholinergic hepatic CPS toxicity.
11 Toxicol Appl Pharmacol. 2017 Dec 15; 337:67–75. doi: 10.1016/j.taap.2017.10.019. Epub 2017 Oct Chlorpyrifos dose used exceeds the in vivo NOAELs for 31. cholinesterase inhibition in mice. The study provides no additional useful data on low dose chlorpyrifos effects. Effects of acute exposure to chlorpyrifos on cholinergic and non-cholinergic targets in normal and high-fat fed male C57BL/6J mice. Kondakala S, Lee JH, Ross MK, Howell GE 3rd. The prevalence of obesity is increasing at an alarming rate in the United States with 36.5% of adults being classified as obese. Compared to normal individuals, obese individuals have noted pathophysiological alterations which may alter the toxicokinetics of xenobiotics and therefore alter their toxicities. However, the effects of obesity on the toxicity of many widely utilized pesticides has not been established. Therefore, the present study was designed to determine if the obese APPENDIX 2 79
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phenotype altered the toxicity of the most widely used organophosphate (OP) insecticide, chlorpyrifos (CPS). Male C57BL/6J mice were fed normal or high-fat diet for 4weeks and administered a single dose of vehicle or CPS (2.0mg/kg; oral gavage) to assess cholinergic (acetylcholinesterase activities) and non-cholinergic (carboxylesterase and endocannabinoid hydrolysis) endpoints. Exposure to CPS significantly decreased red blood cell acetylcholinesterase (AChE) activity, but not brain AChE activity, in both diet groups. Further, CPS exposure decreased hepatic carboxylesterase activity and hepatic hydrolysis of a major endocannabinoid, anandamide, in a diet-dependent manner with high-fat diet fed animals being more sensitive to CPS-mediated inhibition. These in vivo studies were corroborated by in vitro studies using rat primary hepatocytes, which demonstrated that fatty acid amide hydrolase and CES activities were more sensitive to CPS- mediated inhibition than 2-arachidonoylglycerol hydrolase activity. These data demonstrate hepatic CES and FAAH activities in high-fat diet fed mice were more potently inhibited than those in normal diet fed mice following CPS exposure, which suggests that the obese phenotype may exacerbate some of the non-cholinergic effects of CPS exposure.
12 Toxicol Ind Health. 2016 Jul; 32(7):1179–96. doi: 10.1177/0748233714548207. Epub 2014 Sep 18. There are reporting inadequacies regarding the dose actually used in the study. Ameliorative effect of vitamin E to mouse dams and their pups following exposure of mothers to chlorpyrifos during gestation and lactation periods. In the chemicals description in the paper, the following is stated: Mansour SA, Gamet-Payrastre L. ‘High-purity PESTANAL1 Analytical Standard of CPF Pesticides are omnipresent in environment, water, fruits, and vegetables and are considered as risk (99.2%(was purchased from Fluka (Riedel-de Haën, France) factors for human health. Consumers are mainly exposed to pesticides through diet, and the main and added as a component of rodent nuggets at a dose of 50 question to be answered concerns the impact of such exposure on health. In this study, we mg/kg of food. This dose allowed the mice to ingest the developed a mouse model to mimic consumer exposure. During gestation and lactation periods, the equivalent of the acceptable daily intake for CPF (0.01 mg/kg experimental mouse dams (M) received one of the following treatments: (a) diet-free of pesticides; body weight (b.w.)/day), based on previous estimate of (b) diet enriched with chlorpyrifos (CPF; 44.0 μg kg(-1)); c) diet + oral vitamin E (vit. E; α- average food consumption per mouse (Merhi et al, 2010). tocopherol; 200 mg/kg/mouse); and (d) diet enriched with CPF (44.0 μg/kg + oral vit. E (200 The acceptable daily intake was as defined for humans by mg/kg/mouse). At weaning, pups (P) and dams were killed, and organs as well as blood samples the Joint Food and Agriculture Organization/World Health were collected. Compared with control results, CPF induced alteration of measured parameters (eg Organization Meeting on Pesticide Residues (JMPR, 2005) organ weight, alkaline phosphatase, urea, malondialdehyde, superoxide dismutase, and and extrapolated to mice on the basis of mean b.w. cholinesterase) either in mouse dams or in their offspring. Also, CPF induced histological Information on the toxicity of the pesticide was obtained from impairment in kidney, liver, and ovary. Administration of vit. E in conjunction with CPF clearly Extoxnet (1996).’ alleviated deviation of these parameters than those of control ones. In conclusion, a dietary 80 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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exposure of mice during gestation and lactation to low dose of CPF led to significant changes in the In the experimental design description in the paper, the mother but also in the weaned animals that have not been directly exposed to this pesticide. These following is stated: biological and histological modifications could be reversed by an oral supplementation of vit. E. ‘All the 16 individually housed dams with their pups were segregated into 4 different groups with 4 animals in each group. During gestation and lactation periods, the experimental mouse dams (M) received one of the following treatments: (a) diet free of pesticides C (M); (b) diet enriched with CPF; 44.0 µg/kg CPF (M); (c) diet free of pesticides + oral vit. E (α-tocopherol); 200 mg/kg/mouse V (M); and (d) diet enriched with CPF; 44.0 µg/kg + oral vit. E; 200 mg /kg/mouse CPF/V (M). The dose of vit. E was divided into two equal portions and given twice a week. Pups (P) of the experimental dams were designated as C (P), CPF (P), V (P), and CPF/V (P), to sign control, CPF, vit. E, and vit. E + CPF- treated groups, respectively. At the end of weaning, blood samples were taken from the facial artery of each animal (mothers and pups).’ Critically, the actual level of food consumption in the study was not measured. Accordingly the dosimetrics of the study are considered to be unreliable. Adding weight to this conclusion was the fact that plasma cholinesterase was significantly (p < 0.05) inhibited in the chlorpyrifos only treated animals (mean 2831 U/L) cf. the negative control group (3581 U/L). Overall the study is not regarded as being reliable. Furthermore, the effects observed were associated with the presence of inhibition of plasma cholinesterase. The study has no value for evaluation of low dose chlorpyrifos effects.
13 ASN Neuro. 2016 Jun 30; 8(3). pii: 1759091416656253. doi: 10.1177/1759091416656253. Print Dosimetry: ‘To determine the effects of reduced reelin 2016 Jun. expression and CPO exposure on gross morphology, protein expression, and dendritic spine distribution, C57Bl/6 female APPENDIX 2 81
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A Complex Interaction Between Reduced Reelin Expression and Prenatal Organophosphate mice were crossed with heterozygous male reeler mice Exposure Alters Neuronal Cell Morphology. (B6C3Fe-a/a-RelnRl/+) originally obtained from the Jackson Laboratory (Bar Harbor, ME, USA); these mice are referred Mullen BR, Ross B, Chou JW, Khankan R, Khialeeva E, Bui K, Carpenter EM. to as Rl+/− throughout the text. At gestational Day 13.5, Genetic and environmental factors are both likely to contribute to neurodevelopmental disorders pregnant females were implanted with osmotic minipumps including schizophrenia, autism spectrum disorders, and major depressive disorders. Prior studies loaded with 6 mg/ml (20 mg/kg) of CPO (or a vehicle control) from our laboratory and others have demonstrated that the combinatorial effect of two factors- as previously described. This dose corresponds to that used reduced expression of reelin protein and prenatal exposure to the organophosphate pesticide by other groups (Laviola et al, 2006) and is well below the chlorpyrifos oxon-gives rise to acute biochemical effects and to morphological and behavioural reported LD50 of 60 mg/kg.’ phenotypes in adolescent and young adult mice. In the current study, we examine the The authors have also claimed that ‘20 mg/kg corresponds to consequences of these factors on reelin protein expression and neuronal cell morphology in adult a moderate environmental exposure for humans.’ Such mice. While the cell populations that express reelin in the adult brain appear unchanged in location claims are not correct, even for mixing, loacceptable daily and distribution, the levels of full length and cleaved reelin protein show persistent reductions intakeng and application, under Australian conditions. following prenatal exposure to chlorpyrifos oxon. Cell positioning and organization in the Notably this dose is > 6600 times the current Australian hippocampus and cerebellum are largely normal in animals with either reduced reelin expression or acceptable daily intake of 0.003 mg/kg bw/day. prenatal exposure to chlorpyrifos oxon, but cellular complexity and dendritic spine organization is altered, with a skewed distribution of immature dendritic spines in adult animals. Paradoxically, Chlorpyrifos dose used exceeds the in vivo NOAELs for combinatorial exposure to both factors appears to generate a rescue of the dendritic spine cholinesterase inhibition in mice. The study provides no phenotypes, similar to the mitigation of behavioural and morphological changes observed in our additional useful data on low dose chlorpyrifos effects. prior study. Together, our observations support an interaction between reelin expression and chlorpyrifos oxon exposure that is not simply additive, suggesting a complex interplay between genetic and environmental factors in regulating brain morphology.
14 Front Behav Neurosci. 2015 Apr 29; 9:110. doi: 10.3389/fnbeh.2015.00110. eCollection 2015. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Strain dependent effects of conditioned fear in adult C57Bl/6 and Balb/C mice following postnatal additional useful data on low dose chlorpyrifos effects. exposure to chlorpyrifos: relation to expression of brain acetylcholinesterase mRNA. Oriel S, Kofman O. Following reports of emotional psychopathology in children and adults exposed to organophosphates, the effects of postnatal chlorpyrifos (CPF) on fear-conditioning and depression- like behaviours were tested in adult mice. Concomitant changes in expression of mRNA for synaptic and soluble splice variants of acetylcholinesterase (AChE) were examined in mouse pups and adults of the Balb/C and C57Bl/6 (B6) strains, which differ in their behavioural and hormonal stress 82 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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response. Mice were injected subcutaneously with 1 mg/kg CPF on postnatal days 4–10 and tested as adults for conditioned fear, sucrose preference, and forced swim. Acetylcholinesterase activity was assessed in the brains of pups on the first and last day of treatment. Expression of soluble and synaptic AChE mRNA was assessed in brains of treated pups and fear-conditioned adults using real-time PCR. Adult Balb/C mice exposed postnatally to CPF showed exacerbated fear- conditioning and impaired active avoidance. Adult B6 mice exposed postnatally to CPF showed a more specific fear response to tones and less freezing in the inter-tone intervals, in contrast to the vehicle-pretreated mice. Chlorpyrifos also attenuated sweet preference and enhanced climbing in the forced swim test. Chlorpyrifos-treated mice had increased expression of both synaptic and readthrough AChE transcripts in the hippocampus of Balb/C mice and decreased expression in the amygdala following fear-conditioning. In conclusion, postnatal CPF had long-term effects on fear and depression, as well as on expression of AChE mRNA. These changes may be related to alteration in the interaction between hippocampus and amygdala in regulating negative emotions.
15 Int J Mol Sci. 2017 Nov 20; 18(11). pii: E2467. doi: 10.3390/ijms18112467. Chlorpyrifos produced a mixed pattern of up-and down- regulation of genes, which was more evident in the groups Specific Effects of Chronic Dietary Exposure to Chlorpyrifos on Brain Gene Expression-A Mouse treated with a higher chlorpyrifos concentration (10 Study. mg/kg/day). Effects on gene expression occurred at doses ≥ Pallotta MM, Ronca R, Carotenuto R, Porreca I, Turano M, Ambrosino C, Capriglione T. 1 mg/kg bw/day ie at doses higher than the thresholds for inhibition of blood cholinesterases in mice. The majority of Chlorpyrifos (CPF) is an organophosphate insecticide used to control pests on a variety of food and the down-regulated transcripts belonged to proteins involved feed crops. In mammals, maternal exposure to CPF has been reported to induce cerebral cortex in synaptic transmission and plasticity, GABAergic and thinning, alteration of long-term brain cognitive function, and Parkinson-like symptoms, but the dopaminergic signalling. The total number of gene networks mechanisms of these processes are not fully understood. In this study, we aimed to gain a deeper affected sharply reduced at 8 months, and understanding of the alterations induced in the brains of mice chronically exposed to CPF by dietary acetylcholinesterase values shifted from highly inhibited— intake. For our purpose, we analysed F1 offspring (sacrificed at 3 and 8 months) of Mus musculus, approximately 80% in 3-month-old mice—to 30% in the treated in utero and postnatally with 3 different doses of CPF (0.1-1-10 mg/kg/day). Using RT² eldest mice. Profiler PCR Arrays, we evaluated the alterations in the expression of 84 genes associated with neurodegenerative diseases. In the brains of exposed mice, we evidenced a clear dose-response relationship for AChE inhibition and alterations of gene expression. Some of the genes that were steacceptable daily intakely down-regulated, such as Pink1, Park 2, Sv2b, Gabbr2, Sept5 and Atxn2, were directly related to Parkinson's onset. Our experimental results shed light APPENDIX 2 83
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on the possibility that long-term CPF exposure may exert membrane signalling alterations which make brain cells more susceptible to develop neurodegenerative diseases.
16 Physiol Behav. 2015 May 15; 144:37–45. doi: 10.1016/j.physbeh.2015.03.006. Epub 2015 Mar 5. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Chronic exposure to chlorpyrifos triggered body weight increase and memory impairment depending additional useful data on low dose chlorpyrifos effects. on human apoE polymorphisms in a targeted replacement mouse model. Peris-Sampedro F, Basaure P, Reverte I, Cabré M, Domingo JL, Colomina MT. Despite restrictions on their use, humans are still constantly exposed to organophosphates (OPs). A huge number of studies have ratified the neurotoxic effects of chlorpyrifos (CPF) and suggested its association with neurodegenerative diseases, but data are still scarce. Human apolipoprotein E (apoE) plays an important role in lipid transport and distribution. In humans, the apoE4 isoform has been linked to an increased risk of Alzheimer's disease (AD). ApoE3 is the most prevalent isoform worldwide, and has been often established as the healthful one. The current study, performed in targeted replacement (TR) adult male mice, aimed to inquire whether genetic variations of the human apoE respond differently to a chronic dietary challenge with CPF. At four/five months of age, mice carrying apoE2, apoE3 or apoE4 were pair-fed a diet supplemented with CPF at 0 or 2mg/kg body weight/day for 13weeks. Cholinergic signs were monitored daily and body weight changes weekly. In the last week of treatment, learning and memory were assessed in a Barnes maze task. Dietary CPF challenge increased body weight only in apoE3 mice. Differences in the acquisition and retention of the Barnes maze were attributed to apoE genetic differences. Our results showed that apoE4 mice performed worse than apoE2 and apoE3 carriers in the acquisition period of the spatial task, and that apoE2 mice had poorer retention than the other two genotypes. On the other hand, CPF increased the search velocity of apoE2 subjects during the acquisition period. Retention was impaired only in CPF-exposed apoE3 mice. These results underline that gene×environment interactions need to be taken into account in epidemiological studies. Given that apoE3, the most common polymorphism in humans, has proved to be the most sensitive to CPF, the potential implications for human health merit serious thought.
17 Arch Toxicol. 2018 May; 92(5):1717–28. doi: 10.1007/s00204-018-2174-3. Epub 2018 Feb 5. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no additional useful data on low dose chlorpyrifos effects. 84 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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New mechanistic insights on the metabolic-disruptor role of chlorpyrifos in apoE mice: a focus on insulin- and leptin-signalling pathways. Peris-Sampedro F, Blanco J, Cabré M, Basaure P, Guardia-Escote L, Domingo JL, Sánchez DJ, Colomina MT. Recently, we have provided evidence, suggesting that mice expressing the human apolipoprotein E3 (apoE3) are more prone to develop an obesity-like phenotype and a diabetic profile when subchronically fed a chlorpyrifos (CPF)-supplemented diet. The aim of the current study was to examine the underlying mechanisms through which CPF alters both insulin- and leptin-signalling pathways in an APOE-dependent manner. Both adult apoE3- and E4-targeted replacement and C57BL/6 mice were exposed to CPF at 0 or 2 mg/kg body weight/day through the diet for 8 consecutive weeks. We determined the expression of JAK2, p-JAK2, STAT3, p-STAT3, SOCS3, IRS-1, p-IRS-1, AKT, p-AKT, GSK3β, p-GSK3β, and apoE in the liver, as well as hepatic mRNA levels of pon1, pon2, and pon3. CPF markedly disrupted both leptin and insulin homeostasis, particularly in apoE3 mice. Indeed, only CPF-fed apoE3 mice exhibited an increased phosphorylation ratio of STAT3, as well as increased total SOCS3 protein levels. Similarly, the exposure to CPF drastically reduced the phosphorylation ratio of both AKT and GSK3β, especially in apoE3mice. Overall, CPF reduced the expression of the three pon genes, principally in C57BL/6 and apoE3 mice. These results provide notable mechanistic insights on the metabolic effects of the pesticide CPF, and attest the increased vulnerability of apoE3 carriers to its metabolic-disruptor role.
18 Food Chem Toxicol. 2016 Jun; 92:224–35. doi: 10.1016/j.fct.2016.03.029. Epub 2016 Apr 20. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Apolipoprotein E (APOE) genotype and the pesticide chlorpyrifos modulate attention, motivation and additional useful data on low dose chlorpyrifos effects. impulsivity in female mice in the 5-choice serial reaction time task. Peris-Sampedro F, Reverte I, Basaure P, Cabré M, Domingo JL, Colomina MT. Organophosphate pesticides—and chlorpyrifos (CPF) in particular—contribute to a wide range of neurobehavioural disorders. Most experimental research focuses on learning and memory processes, while other behaviours remain understudied. The isoforms of the human apolipoprotein E (apoE) confer different cognitive skills on their carriers, but data on this topic are still limited. The current study was performed to assess whether the APOE genotypic variability differently modulates the effects of CPF on attentional performance, inhibitory control and motivation. Human apoE APPENDIX 2 85
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targeted replacement adult female mice (apoE2, apoE3 and apoE4) were trained to stably perform the 5-choice serial reaction time task (5-CSRTT). Animals were then subjected to daily dietary CPF (3.75 mg/kg body weight) for 4 weeks. After CPF exposure, we established a 4-week CPF-free period to assess recovery. All individuals acquired the task, apoE2 mice showed enhanced learning, while apoE4 mice displayed increased premature and perseverative responding. This genotype- dependent lack of inhibitory control was reversed by CPF. Overall, the pesticide induced protracted impairments in sustained attention and motivation, and it reduced anticipatory responding. ApoE3 mice exhibited delayed attentional disruptions throughout the wash-out period. Taken together, these findings provide notable evidence on the emergence of CPF-related attentional and motivational deficits.
19 Sci Rep. 2016 Dec 1; 6:38131. doi: 10.1038/srep38131. Genomic thyroid toxicity signatures were only detected in vivo at doses ≥ 1 mg/kg bw/day ie above the NOEL for Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes inhibition of blood cholinesterases. Furthermore because of of exposure in vivo. their lower thyroid efficiency, mice are a supersensitive Porreca I, D'Angelo F, De Franceschi L, Mattè A, Ceccarelli M, Iolascon A, Zamò A, Russo F, Ravo model for these types of effects cf. humans. Overall the study M, Tarallo R, Scarfò M, Weisz A, De Felice M, Mallardo M, Ambrosino C. provides no additional useful data on low dose chlorpyrifos effects. In vitro Omics analysis (ie transcriptome) is suggested to predict in vivo toxicity and adverse effects in humans, although the causal link between high-throughput data and effects in vivo is not easily established. Indeed, the chemical-organism interaction can involve processes, such as adaptation, not established in cell cultures. Starting from this consideration we investigate the transcriptomic response of immortalized thyrocytes to ethylenthiourea and chlorpyrifos. In vitro data revealed specific and common genes/mechanisms of toxicity, controlling the proliferation/survival of the thyrocytes and unrelated hematopoietic cell lineages. These results were phenotypically confirmed in vivo by the reduction of circulating T4 hormone and the development of pancytopenia after long exposure. Our data imply that in vitro toxicogenomics is a powerful tool in predicting adverse effects in vivo, experimentally confirming the vision described as Tox21c (Toxicity Testing in the 21st century) although not fully recapitulating the biocomplexity of a living animal.
20 Environ Health. 2015 Apr 2; 14:32. doi: 10.1186/s12940-015-0019-6. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no additional useful data on low dose chlorpyrifos effects. 86 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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Effects of maternal chlorpyrifos diet on social investigation and brain neuroendocrine markers in the offspring—a mouse study. Venerosi A, Tait S, Stecca L, Chiarotti F, De Felice A, Cometa MF, Volpe MT, Calamandrei G, Ricceri L. BACKGROUND: Chlorpyrifos (CPF) is one of the most widely used organophosphate pesticides worldwide. Epidemiological studies on pregnant women and their children suggest a link between in utero CPF exposure and delay in psychomotor and cognitive maturation. A large number of studies in animal models have shown adverse effects of CPF on developing brain and more recently on endocrine targets. Our aim was to determine if developmental exposure to CPF affects social responsiveness and associated molecular neuroendocrine markers at adulthood. METHOD: Pregnant CD1 outbred mice were fed from gestational day 15 to lactation day 14 with either a CPF- added (equivalent to 6 mg/kg/bw/day during pregnancy) or a standard diet. We then assessed in the offspring the long-term effects of CPF exposure on locomotion, social recognition performances and gene expression levels of selected neurondocrine markers in amygdala and hypothalamus. RESULTS: No sign of CPF systemic toxicity was detected. CPF induced behavioural alterations in adult offspring of both sexes: CPF-exposed males displayed enhanced investigative response to unfamiliar social stimuli, whereas CPF-exposed females showed a delayed onset of social investigation and lack of reaction to social novelty. In parallel, molecular effects of CPF were sex dimorphic: in males CPF increased expression of estrogen receptor beta in hypothalamus and decreased oxytocin expression in amygdala; CPF increased vasopressin 1a receptor expression in amygdala in both sexes. CONCLUSIONS: These data indicate that developmental CPF affects mouse social behaviour and interferes with development of sex-dimorphic neuroendocrine pathways with potential disruptive effects on neuroendocrine axes homeostasis. The route of exposure selected in our study corresponds to relevant human exposure scenarios, our data thus supports the view that neuroendocrine effects, especially in susceptible time windows, should deserve more attention in risk assessment of OP insecticides.
21 Pest Manag Sci. 2018 Jun; 74(6):1424–30. doi: 10.1002/ps.4825. Epub 2018 Feb 22. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in mice. The study provides no Chimeric mice with humanized liver as a model for testing organophosphate and carbamate additional useful data on low dose chlorpyrifos effects. pesticide exposure. Suemizu H, Kawai K, Murayama N, Nakamura M, Yamazaki H. APPENDIX 2 87
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BACKGROUND: Diagnosis of acute intoxication with organophosphate (OP) or carbamate (CM) pesticides in humans is achieved by measuring plasma butyrylcholinesterase (BuChE) activity. However, BuChE activity is not an ideal biomarker in experimental animal models. The aim of this study was to establish an experimental mouse model for evaluating exposure to OP and CM pesticides by monitoring BuChE activity using chimeric mice in which the liver was reconstituted with human hepatocytes. RESULTS: A single oral administration of acephate (300 mg/kg), chlorpyrifos (10 mg/kg), fenobucarb (300 mg/kg) or molinate (250 mg/kg) in chimeric mice led to inhibition of >95%, > 95%, 28% and 60% of plasma BuChE activity after 7, 0.5, 0.5 and 7 h, respectively. Dose-dependent decreases in plasma BuChE activity were also observed for acephate and chlorpyrifos. A 5-day repeated-dose study with 10 or 30 mg/kg acephate found a constitutive reduction in plasma BuChE activity to 80% and 70% of pre-dose levels, respectively. CONCLUSION: Changes in plasma BuChE activity in chimeric mice with humanized liver clearly reflected the exposure levels of OP and CM pesticides. These results suggest that the humanized- liver mouse model may be suitable for estimating levels of exposure to these pesticides in humans.
Rat
22 Chem Biol Interact. 2018 Sep 27; 296:105–16. doi: 10.1016/j.cbi.2018.09.016. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Diphenyl diselenide abrogates brain oxidative injury and neurobehavioural deficits associated with additional useful data on low dose chlorpyrifos effects. pesticide chlorpyrifos exposure in rats. Adedara IA, Owoeye O, Awogbindin IO, Ajayi BO, Rocha JBT, Farombi EO. Exposure to pesticide chlorpyrifos (CPF) is associated with neurodevelopmental toxicity both in humans and animals. Diphenyl diselenide (DPDS) is a simple synthetic organoselenium well reported to possess antioxidant, anti-inflammatory and neuroprotective effects. However, there is paucity of information on the beneficial effects of DPDS on CPF-mediated brain injury and neurobehavioural deficits. The present study investigated the neuroprotective mechanism of DPDS in rats sub-chronically treated with CPF alone at 5 mg/kg body weight or orally co-treated with DPDS at 2.5 and 5 mg/kg body weight for 35 consecutive days. Endpoint analyses using video- tracking software in a novel environment revealed that co-treatment with DPDS significantly (p < 0.05) protected against CPF-mediated locomotor and motor deficits precisely the decrease in 88 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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maximum speed, total distance travelled, body rotation, absolute turn angle, forelimb grip strength as well as the increase in negative geotaxis and incidence of fecal pellets. The enhancement in the neurobehavioural activities of rats co-treated with DPDS was verified by track plot analyses. Besides, DPDS assuaged CPF-induced decrease in acetylcholinesterase and antioxidant enzymes activities and the increase in myeloperoxidase activity and lipid peroxidation level in the mid-brain, cerebral cortex and cerebellum of the rats. Histologically, DPDS co-treatment abrogated CPF- mediated neuronal degeneration in the cerebral cortex, dentate gyrus and cornu ammonis3 in the treated rats. In conclusion, the neuroprotective mechanisms of DPDS is related to the prevention of oxidative stress, enhancement of redox status and acetylcholinesterase activity in brain regions of the rats. DPDS may be a promising chemotherapeutic agent against brain injury resulting from CPF exposure.
23 Neurotoxicology. 2017 Mar; 59:183–90. doi: 10.1016/j.neuro.2015.11.016. Epub 2015 Nov 28. Alterations in behaviour (time of emergence from a dark container into a lighted area) were detected following dosing Decreased anxiety in juvenile rats following exposure to low levels of chlorpyrifos during at ≥ 0.5 mg/kg bw/d for 7 days over post-natal days 10–16. development. The LOAEL for this effect was 0.5 mg/kg bw/d which exceeds Carr RL, Armstrong NH, Buchanan AT, Eells JB, Mohammed AN, Ross MK, Nail CA. the NOELs for inhibition of blood cholinesterases used in this report (0.1 mg/kg bw/d) and is equal to the NOEL for brain Exposure to chlorpyrifos (CPF) during the late preweanling period in rats inhibits the cholinesterase in this species (0.5 mg/kg bw/d). Thus the endocannabinoid metabolizing enzymes fatty acid hydrolase (FAAH) and monoacylglycerol lipase findings of this paper support the use of health based (MAGL), resulting in accumulation of their respective substrates anandamide (AEA) and 2- guidance values based on the NOELs for inhibition of blood arachidonylglycerol (2-AG). This occurs at 1.0mg/kg, but at a lower dosage (0.5mg/kg) only FAAH cholinesterases. and AEA are affected with no measurable inhibition of either cholinesterase (ChE) or MAGL. The endocannabinoid system plays a vital role in nervous system development and may be an important developmental target for CPF. The endocannabinoid system plays an important role in the regulation of anxiety and, at higher dosages, developmental exposure to CPF alters anxiety-like behaviour. However, it is not clear whether exposure to low dosages of CPF that do not inhibit ChE will cause any persistent effects on anxiety-like behaviour. To determine if this occurs, 10-day old rat pups were exposed daily for 7 days to either corn oil or 0.5, 0.75, or 1.0mg/kg CPF by oral gavage. At 12h following the last CPF administration, 1.0mg/kg resulted in significant inhibition of FAAH, MAGL, and ChE, whereas 0.5 and 0.75mg/kg resulted in significant inhibition of only FAAH. AEA levels were significantly elevated in all three treatment groups as were palmitoylethanolamide and oleoylethanolamide, which are also substrates for FAAH. 2-AG levels were significantly elevated by 0.75 and 1.0mg/kg but not 0.5mg/kg. On day 25, the latency to emerge from a dark APPENDIX 2 89
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container into a highly illuminated novel open field was measured as an indicator of anxiety. All three CPF treatment groups spent significantly less time in the dark container prior to emerging as compared to the control group, suggesting a decreased level of anxiety. This demonstrates that repeated preweanling exposure to dosages of CPF that do not inhibit brain ChE can induce a decline in the level of anxiety that is detectable during the early postweanling period.
24 Arh Hig Rada Toksikol. 2015 Jun; 66(2):121–7. doi: 10.1515/aiht-2015-66-2624. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no ADHD-like behaviour in the offspring of female rats exposed to low chlorpyrifos doses before additional useful data on low dose chlorpyrifos effects. pregnancy. Grabovska S, Salyha Y. The aim of this study was to investigate how chronic low-dose chlorpyrifos exposure of female Wistar rats before and during pregnancy affects behavioural parameters in their offspring. Four months before pregnancy, we exposed three groups of rats to chlorpyrifos doses of 5, 10, and 15 mg kg-1 body weight every day for 30 days, whereas one group received a single 30 mg kg-1 dose on gestational day 6. When the offspring of the exposed rats grew up, we studied their anxiety rate, motor activity, and cognitive abilities using the respective behavioural tests: open field test, dark/light box, and the extrapolation escape test. The offspring of rats exposed before pregnancy had significantly higher activity rate than controls, and even showed motor agitation and hyperactivity signs. The offspring of rats exposed to the single dose had difficulties solving the extrapolation escape test and showed poorer short- and long-term memory performance. This confirmed that even pre-pregnancy chlorpyrifos exposure can cause neurobehavioural consequences in offspring. Even though the mechanisms of the observed changes remain unclear and need further investigation, these data seem alarming and may serve as an important argument for revising the terms of safe pesticide use.
25 Fiziol Zh. 2015; 61(2):94–101. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no The effect of chronic intoxication with low doses of chlorpyrifos on the behavioural parameters of additional useful data on low dose chlorpyrifos effects. female rats. [Article in Ukrainian; only the English language abstract has been evaluated] 90 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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Grabovska SV, Salyha YT. We explored the effect of chronic chlorpyrifos intake on the behaviour of female laboratory rats. The animals were exposed to chlorpyrifos in doses 5 and 10 mg/kg daily for a month long and tested with behavioural tests: Morris water maze, Open field test, and Dark/light box. Everyday chlorpyrifos intake in dose 10 mg/kg was revealed to cause long- and short-term spatial memory lesion, decrease in total activity, sharp changes in the level of anxiety (it significantly increased at the start of xenobiotic intake and then normalized with time). Similar trends, though less intense, were observed in the group exposed to 5 mg/kg chlorpyrifos. From the survey results it can be concluded that long-term (30 days long) intake of even low doses of chlorpyrifos can cause adverse effects on the functional state of nervous system.
26 J Toxicol Pharmacol. 2017; 1. pii: 018. Epub 2017 Dec 30. Effects of chlorpyrifos or methyl parathion on regional cholinesterase activity and muscarinic receptor subtype binding in juvenile rat brain.
Guo-Ross SX, Meek EC, Chambers JE, Carr RL.
The effects of developmental exposure to two organophosphorus (OP) insecticides, chlorpyrifos
(CPF) and methyl parathion (MPS), on cholinesterase (ChE) activity and muscarinic acetylcholine receptor (mAChR) binding were investigated in preweanling rat brain. Animals were orally gavaged daily with low, medium, and high dosages of the insecticides using an incremental dosing regimen from postnatal day 1 (PND1) to PND20. On PND12, PND17 and PND20, the cerebral cortex, corpus striatum, hippocampus, and medulla-pons were collected for determination of ChE activity, total mAChR density, and the density of the individual mAChR subtypes. ChE activity was inhibited by the medium and high dosages of CPF and MPS at equal levels in all four brain regions at all three ages examined. Exposure to both compounds decreased the levels of the M1, M2/M4, and M3 subtypes and the total mAChR level in all brain regions, but the effects varied by dosage group and Chlorpyrifos dose used exceeds the in vivo NOAELs for brain region. On PND12, only the high dosages induced receptor changes while on PND17 and cholinesterase inhibition in rats. The study provides no PND20, greater effects became evident. In general, the effects on the M1 subtype and total receptor additional useful data on low dose chlorpyrifos effects. levels appeared to be greater in the cerebral cortex and hippocampus than in the corpus striatum and medulla-pons. This did not appear to be the case for the M2/M4 and M3 subtypes effects. The APPENDIX 2 91
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differences between CPF and MPS were minimal even though in some cases, CPF exerted statistically greater effects than MPS did. In general, repeated exposure to organophosphorus insecticides can alter the levels of the various mAChR subtypes in various brain regions which could induce perturbation in cholinergic neurochemistry during the maturation of the brain regions.
27 Neurotoxicology. 2015 Mar; 47:17–26. doi: 10.1016/j.neuro.2015.01.002. Epub 2015 Jan 19. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Repeated exposure to chlorpyrifos leads to prolonged impairments of axonal transport in the living additional useful data on low dose chlorpyrifos effects. rodent brain. Hernandez CM, Beck WD, Naughton SX, Poddar I, Adam BL, Yanasak N, Middleton C, Terry AV Jr. The toxicity of the class of chemicals known as the organophosphates (OP) is most commonly attributed to the inhibition of the enzyme acetylcholinesterase. However, there is significant evidence that this mechanism may not account for all of the deleterious neurologic and neurobehavioural symptoms of OP exposure, especially those associated with levels that produce no overt signs of acute toxicity. In the study described here we evaluated the effects of the commonly used OP-pesticide, chlorpyrifos (CPF) on axonal transport in the brains of living rats using manganese (Mn(2+))-enhanced magnetic resonance imaging (MEMRI) of the optic nerve (ON) projections from the retina to the superior colliculus (SC). T1-weighted MEMRI scans were evaluated at 6 and 24h after intravitreal injection of Mn(2+). As a positive control for axonal transport deficits, initial studies were conducted with the tropolone alkaloid colchicine administered by intravitreal injection. In subsequent studies both single and repeated exposures to CPF were evaluated for effects on axonal transport using MEMRI. As expected, intravitreal injection of colchicine (2.5μg) produced a robust decrease in transport of Mn(2+) along the optic nerve (ON) and to the superior colliculus (SC) (as indicated by the reduced MEMRI contrast). A single subcutaneous (s.c.) injection of CPF (18.0mg/kg) was not associated with significant alterations in the transport of Mn(2+). Conversely, 14-days of repeated s.c. exposure to CPF (18.0mg/kg/day) was associated with decreased transport of Mn(2+) along the ONs and to the SC, an effect that was also present after a 30-day (CPF-free) washout period. These results indicate that repeated exposures to a commonly used pesticide, CPF can result in persistent alterations in axonal transport in the living mammalian brain. Given the fundamental importance of axonal transport to neuronal function, these observations may (at least in part) explain some of the long term neurological deficits that have 92 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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been observed in humans who have been repeatedly exposed to doses of OPs not associated with acute toxicity.
28 Toxicology. 2016 Jan 18; 340:53–62. doi: 10.1016/j.tox.2016.01.001. Epub 2016 Jan 13. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Repeated exposure to neurotoxic levels of chlorpyrifos alters hippocampal expression of additional useful data on low dose chlorpyrifos effects. neurotrophins and neuropeptides. Lee YS, Lewis JA, Ippolito DL, Hussainzada N, Lein PJ, Jackson DA, Stallings JD. Chlorpyrifos (CPF), an organophosphorus pesticide (OP), is one of the most widely used pesticides in the world. Subchronic exposures to CPF that do not cause cholinergic crisis are associated with problems in cognitive function (ie, learning and memory deficits), but the biological mechanism(s) underlying this association remain speculative. To identify potential mechanisms of subchronic CPF neurotoxicity, adult male Long Evans (LE) rats were administered CPF at 3 or 10mg/kg/d (s.c.) for 21 days. We quantified mRNA and non-coding RNA (ncRNA) expression profiles by RNA-seq, microarray analysis and small ncRNA sequencing technology in the CA1 region of the hippocampus. Hippocampal slice immunohistochemistry was used to determine CPF-induced changes in protein expression and localization patterns. Neither dose of CPF caused overt clinical signs of cholinergic toxicity, although after 21 days of exposure, cholinesterase activity was decreased to 58% or 13% of control levels in the hippocampus of rats in the 3 or 10mg/kg/d groups, respectively. Differential gene expression in the CA1 region of the hippocampus was observed only in the 10mg/kg/d dose group relative to controls. Of the 1382 differentially expressed genes identified by RNA-seq and microarray analysis, 67 were common to both approaches. Differential expression of six of these genes (Bdnf, Cort, Crhbp, Nptx2, Npy and Pnoc) was verified in an independent CPF exposure study; immunohistochemistry demonstrated that CRHBP and NPY were elevated in the CA1 region of the hippocampus at 10mg/kg/d CPF. Gene ontology enrichment analysis suggested association of these genes with receptor-mediated cell survival signaling pathways. miR132/212 was also elevated in the CA1 hippocampal region, which may play a role in the disruption of neurotrophin- mediated cognitive processes after CPF administration. These findings identify potential mediators of CPF-induced neurobehavioural deficits following subchronic exposure to CPF at a level that inhibits hippocampal cholinesterase to less than 20% of control. An equally significant finding is that subchronic exposure to CPF at a level that produces more moderate inhibition of hippocampal APPENDIX 2 93
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cholinesterase (approximately 50% of control) does not produce a discernable change in gene expression.
29 Neurotoxicology. 2015 Jan; 46:12–8. doi: 10.1016/j.neuro.2014.11.001. Epub 2014 Nov 20. Chlorpyrifos oxon dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats by chlorpyrifos. The study The cannabinoid receptor antagonist AM251 increases paraoxon and chlorpyrifos oxon toxicity in provides no additional useful data on low dose chlorpyrifos rats. effects. Liu J, Pope C. Organophosphorus anticholinesterases (OPs) elicit acute toxicity by inhibiting acetylcholinesterase (AChE), leacceptable daily intakeng to acetylcholine accumulation and overstimulation of cholinergic receptors. Endocannabinoids (eCBs, eg, arachidonoyl ethanolamide [AEA] and 2-arachidonoyl glycerol [2-AG]) are neuromodulators that regulate neurotransmission by reducing neurotransmitter release. The eCBs are degraded by the enzymes fatty acid amide hydrolase (FAAH, primarily involved in hydrolysis of AEA) and monoacylglycerol lipase (MAGL, primarily responsible for metabolism of 2-AG). We previously reported that the cannabinoid receptor agonist WIN 55,212-2 reduced cholinergic toxicity after paraoxon exposure. This study compared the effects of the cannabinoid receptor antagonist AM251 on acute toxicity following either paraoxon (PO) or chlorpyrifos oxon (CPO). CPO was more potent in vitro than PO at inhibiting AChE (≈ 2 fold), FAAH (≈ 8 fold), and MAGL (≈ 19 fold). Rats were treated with vehicle, PO (0.3 and 0.6 mg/kg, sc) or CPO (6 and 12 mg/kg, sc) and subsets treated with AM251 (3mg/kg, ip; 30 min after OP). Signs of toxicity were recorded for 4h and rats were then sacrificed. OP-treated rats showed dose-related involuntary movements, with AM251 increasing signs of toxicity with the lower dosages. PO and CPO elicited excessive secretions, but AM251 had no apparent effect with either OP. Lethality was increased by AM251 with the higher dosage of PO, but no lethality was noted with either dosage of CPO, with or without AM251. Both OPs caused extensive inhibition of hippocampal AChE and FAAH (>80–90%), but only CPO inhibited MAGL (37–50%). These results provide further evidence that eCB signaling can influence acute OP toxicity. The selective in vivo inhibition of MAGL by CPO may be important in the differential lethality noted between PO and CPO with AM251 co-administration.
30 Neurotoxicology. 2016 Mar; 53:85–92. doi: 10.1016/j.neuro.2015.12.016. Epub 2015 Dec 31. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no additional useful data on low dose chlorpyrifos effects. 94 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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Chronic dietary chlorpyrifos causes long-term spatial memory impairment and thigmotaxic behaviour. López-Granero C, Ruiz-Muñoz AM, Nieto-Escámez FA, Colomina MT, Aschner M, Sánchez-Santed F. Little is known about the long-term effects of chronic exposure to low-level organophosphate (OP) pesticides, and the role of neurotransmitter systems, other than the cholinergic system, in mediating OP neurotoxicity. In this study, rats were administered 5mg/kg/day of chlorpyrifos (CPF) for 6 months commencing at 3-months-of-age. The animals were examined 7 months later (at 16-months- of-age) for spatial learning and memory in the Morris water maze (MWM) and locomotor activity. In addition, we assessed the chronic effects of CPF on glutamatergic and gamma-aminobutyric acid (GABAergic) function using pharmacological challenges with dizocilpine (MK801) and diazepam. Impaired performance related to altered search patterns, including thigmotaxis and long-term spatial memory was noted in the MWM in animals exposed to CPF, pointing to dietary CPF-induced behavioural disturbances, such as anxiety. Twenty-four hours after the 31st session of repeated acquisition task, 0.1mg/kg MK801, an N-methyl-d-aspartate (NMDA) antagonist was intraperitoneally (i.p.) injected for 4 consecutive days. Decreased latencies in the MWM in the control group were noted after two sessions with MK801 treatment. Once the MWM assessment was completed, animals were administered 0.1 or 0.2mg/kg of MK801 and 1 or 3mg/kg of diazepam i.p., and tested for locomotor activity. Both groups, the CPF dietary and control, displayed analogous performance in motor activity. In conclusion, our data point to a connection between the long-term spatial memory, thigmotaxic response and CPF long after the exposure ended.
31 Environ Toxicol Pharmacol. 2018 Apr; 59:17–23. doi: 10.1016/j.etap.2018.02.007. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Epub 2018 Feb 23. additional useful data on low dose chlorpyrifos effects. Alpha lipoic acid protects against chlorpyrifos-induced toxicity in Wistar rats via modulating the apoptotic pathway. Mohamed WR, Mehany ABM, Hussein RM. The chronic exposure to chlorpyrifos (CPF) pesticide induces several human disorders including hepatotoxicity. Alpha-lipoic acid (ALA) is a natural antioxidant compound found in plants and animals. APPENDIX 2 95
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The present study aimed to investigate the possible protective effect of ALA against CPF-induced hepatotoxicity and the possible underlying molecular mechanism. Thirty-two male Wistar rats were divided into: Normal rats received only vehicle; ALA group received ALA (10 mg/kg, i.p.); CPF group received CPF (18 mg/kg, s.c.) and CPF-ALA group received CPF (18 mg/kg, s.c.) once daily for 14 days. The present results demonstrated that administration of ALA significantly improved liver functions (p < 0.05) and limited the histopathological lesions induced by CPF in liver tissues. Furthermore, ALA decreased hepatic malondialdehyde contents while increased the glutathione peroxidase, catalase, superoxide dismutase and acetylcholinesterase activities. Interestingly, ALA showed significant antiapoptotic effects through downregulation of Bax and Caspase-3 expression levels. In conclusion, ALA possess protective effects against CPF-induced liver injury through attenuation of apoptosis and oxidative stress.
32 Environ Sci Pollut Res Int. 2016 Jan; 23(2):1852–9. doi: 10.1007/s11356-015-5448-9. Epub 2015 Chlorpyrifos dose used exceeds the in vivo NOAELs for Sep 24. cholinesterase inhibition in rats. The study provides no additional useful data on low dose chlorpyrifos effects. Neuro and renal toxicity induced by chlorpyrifos and abamectin in rats: Toxicity of insecticide mixture. Nasr HM, El-Demerdash FM, El-Nagar WA. Oxidative stress by increased production of reactive oxygen species has been implicated in pesticides toxicity. This study focused on the toxicological effects of chlorpyrifos, an organophosphate insecticide and abamectin, a biocide each alone or in combination on antioxidant status, and oxidative stress biomarkers in brain and kidney. Animals were divided into four groups. The first group was used as control while groups 2, 3, and 4 were treated with chlorpyrifos (CPF; 14.9 mg/kg bw), abamectin (ABM; 30 mg/kg bw), and chlorpyrifos plus abamectin, respectively. Rats were treated daily with the tested compounds by oral gavages for 30 days. Results revealed that thiobarbituric acid-reactive substances (TBARS) levels were significantly increased in brain and kidney due to insecticides administration. On the other hand, reduced glutathione (GSH) and protein contents in addition to the activities of antioxidant enzymes, alkaline phosphatase (ALP), and acetylcholinesterase (AChE) were significantly decreased in rat organs. A significant induction in lactate dehydrogenase (LDH) activity, urea, and creatinine levels were also observed. The response was more pronounced in rats treated with both CPF and ABM. Results showed that the used insecticides had the propensity to cause significant oxidative damage in rat brain and kidney which is associated with marked perturbations in antioxidant defense system. It can be concluded that 96 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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antioxidant enzymes can be used as potential biomarkers of toxicity associated with pesticides exposure.
33 PLoS One. 2016 Oct 19; 11(10):e0164614. doi: 10.1371/journal.pone.0164614. eCollection 2016. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Inulin Supplementation Lowered the Metabolic Defects of Prolonged Exposure to Chlorpyrifos from additional useful data on low dose chlorpyrifos effects. Gestation to Young Adult Stage in Offspring Rats. Reygner J, Lichtenberger L, Elmhiri G, Dou S, Bahi-Jaber N, Rhazi L, Depeint F, Bach V, Khorsi- Cauet H, Abdennebi-Najar L. Increasing evidence indicates that chlorpyrifos (CPF), an organophosphorus insecticide, is involved in metabolic disorders. We assess the hypothesis whether supplementation with prebiotics from gestation to adulthood, through a modulation of microbiota composition and fermentative activity, alleviates CPF induced metabolic disorders of 60 days old offspring. 5 groups of Wistar rats, from gestation until weaning, received two doses of CPF pesticide: 1 mg/kg/day (CPF1) or 3.5 mg/kg/day (CPF3.5) with free access to inulin (10g/L in drinking water). Then male pups received the same treatment as dams. Metabolic profile, leptin sensitivity, insulin receptor (IR) expression in liver, gut microbiota composition and short chain fatty acid composition (SCFAs) in the colon, were analyzed at postnatal day 60 in the offspring (PND 60). CPF3.5 increased offspring's birth body weight (bw) but decreased bw at PND60. Inulin supplementation restored the bw at PND 60 to control levels. Hyperinsulinemia and decrease in insulin receptor β in liver were seen in CPF1 exposed rats. In contrast, hyperglycemia and decrease in insulin level were found in CPF3.5 rats. Inulin restored the levels of some metabolic parameters in CPF groups to ranges comparable with the controls. The total bacterial population, short chain fatty acid (SCFA) production and butyrate levels were enhanced in CPF groups receiving inulin. Our data indicate that developmental exposure to CPF interferes with metabolism with dose related effects evident at adulthood. By modulating microbiota population and fermentative activity, inulin corrected adult metabolic disorders of rats exposed to CPF during development. Prebiotics supply may be thus considered as a novel nutritional strategy to counteract insulin resistance and diabetes induced by a continuous pesticide exposure.
34 Ukr Biochem J. 2015 Sep-Oct; 87(5):124–32. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no additional useful data on low dose chlorpyrifos effects. APPENDIX 2 97
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Changes in glutathione system and lipid peroxidation in rat blood during the first hour after chlorpyrifos exposure. Rosalovsky VP, Grabovska SV, Salyha YT. Chlorpyrifos (CPF) is a highly toxic organophosphate compound, widely used as an active substance of many insecticides. Along with the anticholinesterase action, CPF may affect other biochemical mechanisms, particularly through disrupting pro- and antioxidant balance and inducing free-racceptable daily intakecal oxidative stress. Origins and occurrence of these phenomena are still not fully understood. The aim of our work was to investigate the effects of chlorpyrifos on key parameters of glutathione system and on lipid peroxidation in rat blood in the time dynamics during one hour after exposure. We found that a single exposure to 50 mg/kg chlorpyrifos caused a linear decrease in butyryl cholinesterase activity, increased activity of glutathione peroxidase and glutathione reductase, alterations in the levels of glutathione, TBA-active products and lipid hydroperoxides during 1 hour after poisoning. The most significant changes in studied parameters were detected at the 15–30th minutes after chlorpyrifos exposure.
35 Neurotoxicology. 2015 Sep; 50:149–56. doi: 10.1016/j.neuro.2015.08.010. Epub 2015 Aug 19. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Low-level repeated exposure to diazinon and chlorpyrifos decrease anxiety-like behaviour in adult additional useful data on low dose chlorpyrifos effects. male rats as assessed by marble burying behaviour. Savy CY, Fitchett AE, McQuade R, Gartside SE, Morris CM, Blain PG, Judge SJ. Occupational exposure to organophosphate (OPs) pesticides is reported to increase in the risk of developing anxiety and depression. Preclinical studies using OP levels, which inhibit acetylcholinesterase activity, support the clinical observations, but little is known of the effects of exposure below this threshold. We examined the effects of low level OP exposure on behaviours and neurochemistry associated with affective disorders. Adult rats were administered either diazinon (1 mg/kg i.p.) which is present in sheep dip and flea collars, chlorpyrifos (1 mg/kg i.p.) which is present in crop sprays, or vehicle for 5 days. OP exposure did not affect acetylcholinesterase activity (blood, cerebellum, caudate putamen, hippocampus, prefrontal cortex), anhedonia-like behaviour (sucrose preference), working memory (novel object recognition), locomotor activity or anxiety-like behaviour in the open field arena. In contrast OP exposure attenuated marble burying behaviour, an ethological measure of anxiety. The diazinon-induced reduction in marble burying 98 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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persisted after exposure cessation. In comparison to vehicle, dopamine levels were lowered by chlorpyrifos, but not diazinon. 5-HT levels and turnover were unaffected by OP exposure. However, 5-HT transporter expression was reduced by diazinon suggesting subtle changes in 5-HT transmission. These data indicate exposure to occupational and domestic OPs, below the threshold to inhibit acetylcholinesterase, can subtly alter behaviour and neurochemistry.
36 Toxicol Sci. 2018 Sep 1; 165(1):244–53. doi: 10.1093/toxsci/kfy158. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no The Organophosphorus Pesticide Chlorpyrifos Induces Sex-Specific Airway Hyperreactivity in Adult additional useful data on low dose chlorpyrifos effects. Rats. Shaffo FC, Grodzki AC, Schelegle ES, Lein PJ. Occupational and environmental exposures to organophosphorus pesticides (OPs) are associated with increased incidence of asthma and other pulmonary diseases. Although the canonical mechanism of OP neurotoxicity is inhibition of acetylcholinesterase (AChE), it was previously reported that the OP chlorpyrifos (CPF) causes airway hyperreactivity (AHR) in guinea pigs at levels that do not inhibit lung or brain AChE. The guinea pig is considered to have inherently hyperresponsive airways, thus, cross-species validation is needed to confirm relevance to humans. Additionally, sex differences in asthma incidence have been demonstrated in the human population, but whether OP-induced AHR is sex-dependent has not been systematically studied in a preclinical model. In this study, 8-week old male and female Sprague Dawley rats were administered CPF at doses causing comparable AChE inhibition in whole lung homogenate (30 mg/kg in males, 7 mg/kg in females, sc) prior to assessing pulmonary mechanics in response to electrical stimulation of the vagus nerves at 24 h, 48 h, 72 h, 7 d or 14 d post-exposure in males, and 24 h or 7 d post-exposure in females. CPF significantly potentiated vagally induced airway resistance and tissue elastance at 7 d post-exposure in males, and at 24 h and 7 d post-exposure in females. These effects occurred independent of significant AChE inhibition in cerebellum, blood, trachealis, or isolated airway, suggesting that AChE independent OP-induced airway hyperreactivity is a cross-species phenomenon. These findings have significant implications for assessing the risk posed by CPF, and potentially other OPs, to human health and safety. APPENDIX 2 99
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37 Springerplus. 2016 Aug 12; 5(1):1344. doi: 10.1186/s40064-016-3004-9. eCollection 2016. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Induction of neurotoxicity by organophosphate pesticide chlorpyrifos and modulating role of cow additional useful data on low dose chlorpyrifos effects. urine. Sharma S, Chadha P. INTRODUCTION: Organophosphate pesticides are among the most widely used synthetic chemicals for controlling a wide variety of pests and for domestic purposes. Among these chlorpyrifos (CPF) is the most extensively used pesticide throughout the world, including India. OBJECTIVE: The present study was undertaken to examine the neurotoxicity induced by CPF and modulatory effect of cow urine as a natural antioxidant alternative to reduce the neurotoxic effects of CPF. DESIGN: For this purpose LD50 was determined and one fourth of LD50 was selected (38 mg/kg body weight (b.wt)) for treatment of rats. The antioxidant level of cow urine was determined by ABTS assay. RESULTS: Exposure to pesticides resulted in significant reduction in the acetylcholinestrase (AChE) activity (P ≤ 0.01). However, groups pretreated with cow urine had improved levels of AChE activity as compared to CPF treated groups. CONCLUSION: Thus, the present findings clearly show that oral CPF has the propensity to cause significant neurotoxicity in rat brains while cow urine treatment alleviates CPF induced toxicity to a greater extent. In addition, AChE can be used as a potential biomarker of toxicity associated with pesticide exposure.
38 Environ Sci Pollut Res Int. 2017 Jan; 24(1):381–7. doi: 10.1007/s11356-016-7799-2. Epub 2016 Oct Chlorpyrifos dose used exceeds the in vivo NOAELs for 8. cholinesterase inhibition in rats. The study provides no additional useful data on low dose chlorpyrifos effects. Chlorpyrifos pollution: its effect on brain acetylcholinesterase activity in rat and treatment of polluted soil by indigenous Pseudomonas sp. Sharma S, Singh PB, Chadha P, Saini HS. The study was aimed to evaluate the levels of chlorpyrifos (CPF) pollution in agricultural soil of Punjab, India, its detrimental effects on acetylcholinesterase (AChE) activity in rat brain and bioremediation of soils polluted with CPF using indigenous and adapted bacterial lab isolate. The analysis revealed that soil samples of Bathinda and Amritsar regions are highly contaminated with chlorpyrifos showing 19 to 175 mg/kg concentrations of CPF. The non-targeted animals may get poisoned with CPF by its indirect dermal absorption, inhalation of toxic fumes and regular consumption of soiled food grains. The study indicated that even the lowermost concentrations of 100 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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CPF, 19 and 76 mg/kg of soil found in the Amritsar and Bathinda regions respectively can significantly inhibit the AChE activity in rat brain within 24 h of its treatment. This represents the antagonistic effect of CPF on AChE which is a prime neurotransmitter present in all living beings including humans. In light of this, an attempt was made to remediate the polluted soil, a major reservoir of CPF, using Pseudomonas sp. (ChlD), an indigenous bacterial isolate. The culture efficiently degraded 10 to 100 mg/kg chlorpyrifos supplemented in the soil and utilized it as sole source of carbon and energy for its growth. Thus, this study provides a detailed insight regarding the level of CPF pollution in Punjab, its detrimental effects on mammals and bio-based solution to remediate the sites polluted with CPF.
39 Neurosci Lett. 2017 Feb 22; 641:94–100. doi: 10.1016/j.neulet.2017.01.053. Epub 2017 Jan 24. None of these studies are regarded as being of regulatory quality due to inadequacies of the statistical methods used, Chlorpyrifos induces anxiety-like behaviour in offspring rats exposed during pregnancy. lack of blinding of the observer and/or other techniques to Silva JG, Boareto AC, Schreiber AK, Redivo DD, Gambeta E, Vergara F, Morais H, Zanoveli JM, reduce observer bias, lack of assay validation by Dalsenter PR. incorporation of appropriate control groups and lack of historical control data. Because of the regulatory unreliability Chlorpyrifos is a pesticide, member of the organophosphate class, widely used in several countries of the study a NOAEL was not determined. to manage insect pests on many agricultural crops. Currently, chlorpyrifos health risks are being reevaluated due to possible adverse effects, especially on the central nervous system. The aim of this study was to investigate the possible action of this pesticide on the behaviours related to anxiety and depression of offspring rats exposed during pregnancy. Wistar rats were treated orally with chlorpyrifos (0.01, 0.1, 1 and 10mg/kg/day) on gestational days 14–20. Male offspring behaviour was evaluated on post-natal days 21 and 70 by the elevated plus-maze test, open field test and forced swimming test. The results demonstrated that exposure to 0.1, 1 or 10mg/kg/day of chlorpyrifos could induce anxiogenic-like, but not depressive-like behaviour at post-natal day 21, without causing fetal toxicity. This effect was reversed on post-natal day 70.
40 Environ Toxicol. 2016 Aug; 31(8):1017–26. doi: 10.1002/tox.22111. Epub 2015 Apr 10. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no The role of multifunctional drug therapy as an antidote to combat experimental subacute additional useful data on low dose chlorpyrifos effects. neurotoxicity induced by organophosphate pesticides. Singh S, Prakash A, Kaur S, Ming LC, Mani V, Majeed AB. APPENDIX 2 101
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Organophosphate pesticides are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants are potent inhibitors of cholinesterases leacceptable daily intakeng to a massive build-up of acetylcholine which induces an array of deleterious effects, including convulsions, oxidative damage and neurobehavioural deficits. Antidotal therapies with atropine and oxime yield a remarkable survival rate, but fail to prevent neuronal damage and behavioural problems. It has been indicated that multifunction drug therapy with potassium channel openers, calcium channel antagonists and antioxidants (either single-agent therapy or combination therapy) may have the potential to prevent cell death and/or slow down the processes of secondary neuronal damage. The aim of the present study, therefore, was to make a relative assessment of the potential effects of nicorandil (2 mg/kg), clinidipine (10 mg/kg), and grape seed proanthocyanidin (GSPE) extract (200 mg/kg) individually against subacute chlorpyrifos induced toxicity. The test drugs were administered to Wistar rats 2 h after exposure to Chlorpyrifos (CPF). Different behavioural studies and biochemical estimation has been carried in the study. The results showed that chronic administration of CPF significantly impaired learning and memory, along with motor coordination, and produced a marked increase in oxidative stress along with significantly reduced acetylcholine esterase (AChE) activity. Treatment with nicorandil, clinidipine and GSPE was shown to significantly improve memory performance, attenuate oxidative damage and enhance AChE activity in rats. The present study also suggests that a combination of nicorandil, clinidipine, and GSPE has a better neuroprotective effect against subacute CPF induced neurotoxicity than if applied individually. Environ Toxicol 31: 1017–26, 2016.
41 Brain Res Bull. 2015 Jan; 110:54–67. doi: 10.1016/j.brainresbull.2014.12.003. Epub 2014 Dec 12. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Prenatal nicotine alters the developmental neurotoxicity of postnatal chlorpyrifos directed toward additional useful data on low dose chlorpyrifos effects. cholinergic systems: better, worse, or just "different?”. However, the study does illustrate the potentially important Slotkin TA, Seidler FJ. interaction between nicotine and chlorpyrifos in terms of This study examines whether prenatal nicotine exposure sensitizes the developing brain to neurodevelopment. Nicotine contained in tobacco smoke subsequent developmental neurotoxicity evoked by chlorpyrifos, a commonly-used insecticide. We produces abnormalities of brain development leacceptable gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels daily intakeng to neurobehavioural deficits such as attention typical of smokers; offspring were then given chlorpyrifos on postnatal days 1–4, at a dose (1mg/kg) deficit/hyperactivity disorder, conduct disorder and affective that produces minimally-detectable inhibition of brain cholinesterase activity. We evaluated indices disorders ie the effects of nicotine exposure overlap the for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of Ach projections and cell bodies; we measured 102 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and claimed neurodevelopmental effects of low dose chlorpyrifos choline acetyltransferase activity, all known targets for the adverse developmental effects of exposure in children. nicotine and chlorpyrifos given individually. By itself nicotine elicited overall upregulation of the ACh ‘prenatal nicotine administration alters the subsequent markers, albeit with selective differences by sex, region and age. Likewise, chlorpyrifos alone had developmental neurotoxicity of chlorpyrifos in a complex highly sex-selective effects. Importantly, all the effects showed temporal progression between manner, comprising sex-specific, regional and temporal adolescence and adulthood, pointing to ongoing synaptic changes rather than just persistence after effects on the expression of the synaptic proteins that most an initial injury. Prenatal nicotine administration altered the responses to chlorpyrifos in a consistent closely delineate ACh function. Despite that complexity, there pattern for all three markers, lowering values relative to those of the individual treatments or to was a clear overall pattern. The combined exposure always those expected from simple additive effects of nicotine and chlorpyrifos. The combination produced lowered values relative to those of the individual treatments global interference with emergence of the ACh phenotype, an effect not seen with nicotine or or to the values expected from simple additive effects, chlorpyrifos alone. Given that human exposures to nicotine and chlorpyrifos are widespread, our producing a unique, global interference with emergence of results point to the creation of a subpopulation with heightened vulnerability. the ACh phenotype, an effect not seen with nicotine or chlorpyrifos alone. Depending upon sex, age and region, nicotine or chlorpyrifos by themselves evoked both increases and decreases in expression of nAChRs, the high-affinity presynaptic choline transporter and ChAT. Consequently, where an individual treatment evoked an increase in a given parameter, the superimposed reduction from combined treatment appeared to “protect” by restoring those values closer to normal. However, our results show quite clearly that this is probably not protection against the initial brain injury, but rather a failure of adaptive responses: in every case, the effects on ACh parameters showed progressive changes between adolescence and adulthood, not persistence of an initial effect.’
42 Brain Res Bull. 2015 Feb; 111:84–96. doi: 10.1016/j.brainresbull.2015.01.003. Epub 2015 Jan 12. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Prenatal nicotine changes the response to postnatal chlorpyrifos: Interactions targeting serotonergic additional useful data on low dose chlorpyrifos neurological synaptic function and cognition. effects. Slotkin TA, Skavicus S, Levin ED, Seidler FJ. APPENDIX 2 103
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Nicotine and chlorpyrifos are developmental neurotoxicants that target serotonin systems. We However, the study does illustrate the potentially important examined whether prenatal nicotine exposure alters the subsequent response to chlorpyrifos given interaction between nicoine and chlorpyrifos in terms of postnatally. Pregnant rats received nicotine throughout gestation at 3mg/kg/day, a regimen neurodevelopment. designed to achieve plasma levels seen in smokers; chlorpyrifos was given to pups on postnatal ‘…….that prenatal nicotine treatment changes the response days (PN) 1–4 at 1mg/kg, just above the detection threshold for brain cholinesterase inhibition. We of 5HT systems to subsequent chlorpyrifos exposure, assessed long-term effects from adolescence (PN30) through full adulthood (PN150), measuring the specifically leacceptable daily intakeng to impairment of expression of serotonin receptors and serotonin turnover (index of presynaptic impulse activity) in adaptive increases in 5HT receptors and presynaptic activity; cerebrocortical brain regions encompassing the projections that are known targets for nicotine and hence the combined treatment produces a global interference chlorpyrifos. Nicotine or chlorpyrifos individually increased the expression of serotonin receptors, with 5HT synaptic function not seen with either agent alone. with greater effects on males than on females and with distinct temporal and regional patterns Because the unique effect is superimposed on the direct indicative of adaptive synaptic changes rather than simply an extension of initial injury. This actions of each toxicant, the smaller upregulation of 5HT interpretation was confirmed by our finding an increase in serotonin turnover, connoting presynaptic receptors could be mistaken for partial neuroprotection by serotonergic hyperactivity. Animals receiving the combined treatment showed a reduction in these nicotine, but evaluation of presynaptic activity and of the adaptive effects on receptor binding and turnover relative to the individual agents, or even an effect temporal, regional and sex-dependent patterns indicates in the opposite direction; further, normal sex differences in serotonin receptor concentrations were otherwise. This mirrors our conclusions for the effects of dissipated or reversed, an effect that was confirmed by behavioural evaluations in the Novel nicotine on the developmental neurotoxicity of chlorpyrifos Objection Recognition Test. In addition to the known liabilities associated with maternal smoking directed toward cholinergic pathways (Slotkin and Seidler, during pregnancy, our results point to additional costs in the form of heightened vulnerability to 2015) and resembles our findings for prenatal neurotoxic chemicals encountered later in life. dexamethasone treatment, which likewise interfered with adaptive responses to chlorpyrifos, thus augmenting the deterioration of synaptic function and behavioural performance (Levin et al, 2014; Slotkin et al, 2013, 2014). In addition to the known liabilities associated with maternal smoking during pregnancy, our results point to additional costs in the form of heightened vulnerability to neurotoxic chemicals encountered later in life.’
43 Toxicology. 2015 Dec 2; 338:8–16. doi: 10.1016/j.tox.2015.09.005. Epub 2015 Sep 28. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos. additional useful data on low dose chlorpyrifos neurological Slotkin TA, Skavicus S, Seidler FJ. effects. 104 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the However, the study does illustrate the potentially important developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose interactions between nicotine or dexamethasone (common (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on prenatal drug exposures) and chlorpyrifos and postnatal days 1–4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain neurodevelopment. cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17–19 at a standard therapeutic dose (0.2mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar β- adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants.
44 Biomed Pharmacother. 2017 Apr; 88:844–51. doi: 10.1016/j.biopha.2017.01.105. Epub 2017 Feb 4. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Immunoprotective activity and antioxidant properties of cactus (Opuntia ficus indica) extract against additional useful data on low dose chlorpyrifos neurological chlorpyrifos toxicity in rats. effects. Smida A, Ncibi S, Taleb J, Ben Saad A, Ncib S, Zourgui L. Opuntia ficus indica (family Cactaceae) is a typical Mediterranean plant, mainly used in food and tracceptable daily intaketional folk medicine. The present study was designed to evaluate the protective effect of Opuntia ficus indica extract against chlorpyrifos (CPF)-induced immunotoxicity in rats. The experimental animals consisted of four groups of Wistar rats (5-6 weeks old) of eight each: a control group, a group treated with CPF (10mg/kg), a group treated with Opuntia ficus indica extract (100mg/kg), and a group treated with cactus extract then treated with CPF. These components were daily administered by gavage for 30 days. After treatment, immunotoxicity was estimated by a count of thymocytes, splenocytes, stem cells in the bone marrow, relative weights of APPENDIX 2 105
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thymus and spleen, DNA aspects, and oxidative stress status in these organs. Results showed that CPF could induce thymus atrophy, splenomegaly, and a decrease in the cell number in the bone marrow. It also increased the oxidative stress markers resulting in elevated levels of the lipid peroxidation with a concomitant decrease in the levels of enzymatic antioxidants (SOD, CAT, GPx) in both spleen and thymus, and also degradation of thymocyte and splenocyte DNA. Consistent histological changes were found in the spleen and thymus under CPF treatment. However, administration of Opuntia ficus indica extract was found to alleviate this CPF-induced damage.
45 Pol J Vet Sci. 2016; 19(2):371–8. doi: 10.1515/pjvs-2016-0046. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Concentration of hepatic vitamins A and E in rats exposed to chlorpyrifos and/or enrofloxacin. additional useful data on low dose chlorpyrifos neurological Spodniewska A, Barski D. effects. The aim of the study was to determine the level of antioxidant vitamins A and E in the liver of rats exposed to chlorpyrifos and/or enrofloxacin. Chlorpyrifos (Group I) was administered at a dose of 0.04 LD50 (6 mg/kg b.w.) for 28 days, and enrofloxacin (Group II) at a dose of 5 mg/kg b.w. for 5 consecutive days. The animals of group III were given both of the mentioned above compounds at the same manner as groups I and II, but enrofloxacin was applied to rats for the last 5 days of chlorpyrifos exposure (ie on day 24, 25, 26, 27 and 28). Chlorpyrifos and enrofloxacin were administered to rats intragastrically via a gastric tube. The quantitative determination of vitamins was made by the HPLC method. The results of this study indicated a reduction in the hepatic concentrations of vitamins A and E, compared to the control, which sustained for the entire period of the experiment. The four-week administration of chlorpyrifos to rats resulted in a significant decrease of vitamins in the initial period of the experiment, ie up to 24 hours after exposure. For vitamin A the maximum drop was observed after 24 hours (19.24%) and for vitamin E after 6 hours (23.19%). Enrofloxacin caused a slight (3–9%) reduction in the level of the analysed vitamins. In the chlorpyrifos-enrofloxacin co-exposure group reduced vitamins A and E levels were also noted, but changes in this group were less pronounced in comparison to the animals intoxicated with chlorpyrifos only. The decrease in the antioxidant vitamin levels, particularly noticeable in the chlorpyrifos—and the chlorpyrifos combined with enrofloxacin-treated groups, may result not only from the increase in the concentration of free racceptable daily intakecals, but also from the intensification of the secondary stages of lipid peroxidation. 106 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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46 J Biochem Mol Toxicol. 2018 May; 32(5):e22050. doi: 10.1002/jbt.22050. Epub 2018 Apr 18. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Ameliorative effect of nanoencapsulated flavonoid against chlorpyrifos-induced hepatic oxidative additional useful data on low dose chlorpyrifos neurological damage and immunotoxicity in Wistar rats. effects. Suke SG, Sherekar P, Kahale V, Patil S, Mundhada D, Nanoti VM. The theme of the present work is to evaluate the protective effect of nanoencapsulated quercetin (NEQ) against chlorpyrifos (CPF)-induced hepatic damage and immune alterations in animals. Nanoparticles (NP) drug encapsulation was prepared. 40 male Wistar rats were divided into eight groups. Two groups served as control and CPF (13.5 mg/kg) treatment for 28 days. Other three groups were free quercetin (QC), NP and NEQ treated with 3 mg/kg respectively for 15 days; whereas remaining three groups received treatment of CPF and QC, NP, NEQ, respectively, for 15 days. The results show that significantly altered oxidative stress in the liver tissue and liver enzyme parameters in blood and immune responses in CPF-treated rats compared to controls. Administration of NEQ attenuated biochemical and immunological parameters. The liver histopathological analysis confirmed pathological improvement. Hence, use of NEQ appeared to be beneficial to a great extent in attenuating and restoring hepatic oxidative damage and immune alteration sustained by pesticide exposure.
47 Hum Exp Toxicol. 2016 Sep; 35(9):991–1004. doi: 10.1177/0960327115614384. Epub 2015 Oct 30. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no A model of chlorpyrifos distribution and its biochemical effects on the liver and kidneys of rats. additional useful data on low dose chlorpyrifos neurological Tanvir EM, Afroz R, Chowdhury M, Gan SH, Karim N, Islam MN, Khalil MI. effects. This study investigated the main target sites of chlorpyrifos (CPF), its effect on biochemical indices, and the pathological changes observed in rat liver and kidney function using gas chromatography/mass spectrometry. Adult female Wistar rats (n = 12) were randomly assigned into two groups (one control and one test group; n = 6 each). The test group received CPF via oral gavage for 21 days at 5 mg/kg daily. The distribution of CPF was determined in various organs (liver, brain, heart, lung, kidney, ovary, acceptable daily intakepose tissue, and skeletal muscle), urine and stool samples using GCMS. Approximately 6.18% of CPF was distributed in the body tissues, and the highest CPF concentration (3.80%) was found in acceptable daily intakepose tissue. CPF also accumulated in the liver (0.29%), brain (0.22%), kidney (0.10%), and ovary (0.03%). Approximately 83.60% of CPF was detected in the urine. CPF exposure resulted in a APPENDIX 2 107
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significant increase in plasma transaminases, alkaline phosphatase, and total bilirubin levels, a significant reduction in total protein levels and an altered lipid profile. Oxidative stress due to CPF administration was also evidenced by a significant increase in liver malondialdehyde levels. The detrimental effects of CPF on kidney function consisted of a significant increase in plasma urea and creatinine levels. Liver and kidney histology confirmed the observed biochemical changes. In conclusion, CPF bioaccumulates over time and exerts toxic effects on animals.
48 Toxicology. 2015 Dec 2; 338:95–103. doi: 10.1016/j.tox.2015.10.010. Epub 2015 Oct 30. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no The effect of HMGB1 on sub-toxic chlorpyrifos exposure-induced neuroinflammation in amygdala of additional useful data on low dose chlorpyrifos neurological neonatal rats. effects. Tian J, Dai H, Deng Y, Zhang J, Li Y, Zhou J, Zhao M, Zhao M, Zhang C, Zhang Y, Wang P, Bing G, Zhao L. Chlorpyrifos (CPF), one of organophosphorus pesticides (OPs), is associated with developmental neurotoxicity. Inflammatory response is closely related with CPF-induced neurotoxicity. The present study aimed at exploring whether sub-toxic CPF exposure on neonatal rats results in neuroinflammation that mediated by HMGB1/TLR4/NF-κB signaling pathway in the amygdala. The neonatal rats were subcutaneously injected with 5mg/kg CPF for 4 consecutive days (postnatal day 11–14) with or without HMGB1 inhibitor, glycyrrhizin. We assessed the levels of pro-inflammatory cytokines at 12, 24, and 72 h after CPF exposure. The role of HMGB1 on neuroinflammation in sub- toxic exposure during brain development was studied. CPF-treated neonatal rats exhibited a significant increase in the expression of pro-inflammatory cytokines, such as IL-6, TNF-α and HMGB1, and a significant increase in the activation of NF-κB in the amygdala after CPF exposure. Inhibited HMGB1 reduced the release of IL-6 and TNF-α, and inhibited activation of NF-κB. Our findings indicate that CPF exposure on developmental brain might induce the activation of neuroinflammation mediated by HMGB1/TLR4/NF-κB pathway in the amygdala.
49 Toxicol Ind Health. 2017 Feb; 33(2):159–70. doi: 10.1177/0748233715616553. Epub 2016 Jul 10. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no The protective role of alpha-lipoic acid on long-term exposure of rats to the combination of additional useful data on low dose chlorpyrifos neurological chlorpyrifos and deltamethrin pesticides. effects. Uchendu C, Ambali SF, Ayo JO, Esievo KA. 108 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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The study was aimed at evaluating the protective role of α-lipoic acid (ALA) on long-term exposure of rats to the combination of chlorpyrifos (CPF) and deltamethrin (DLT). Forty-two (42) male Wistar rats were divided into 6 exposure groups with 7 animals in each group: (I) soya oil (2 ml kg-1), (II) ALA (60 mg kg-1), (III) DLT (6.25 mg kg-1), (IV) CPF (4.75 mg kg-1), (V) (CPF + DLT) DLT (6.25 mg kg-1) and CPF (4.75 mg kg-1; 1/20th of the previously determined median lethal dose) and (VI) (ALA + CPF + DLT) pretreated with ALA (60 mg kg-1) and then co-exposed to CPF and DLT, 45 min later. The regimens were administered by gavage once daily for a period of 16 weeks. Sera obtained from blood collected at the end of the experimental period were used for the evaluation of serum glucose, total protein, albumin, urea, creatinine and the activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase and acetylcholinesterase. The liver homogenate was used to assay for the activities of superoxide dismutase and glutathione peroxidase and the concentrations of malondialdehyde, cytokine and tumour necrotic factor α. The result showed that the combination of CPF and DLT resulted in marked alterations of these biochemical parameters in most cases compared to either of the pesticides singly, supplementation with ALA ameliorated these alterations.
50 J Steroid Biochem Mol Biol. 2016 Feb; 156:1–9. doi: 10.1016/j.jsbmb.2015.10.010. Epub 2015 Oct Dosing: 0, 0.01, 1 mg/kg bw/day for 100 days. An unusual 27. vehicle (castor oil) was used. Chlorpyrifos exposure at dose 0.01 mg/kg bw/day were associated with a small, non-dose Pesticide chlorpyrifos acts as an endocrine disruptor in adult rats causing changes in mammary related, significant (p < 0.05) increase in the number of gland and hormonal balance. mammary ducts per histological section without any change Ventura C, Nieto MR, Bourguignon N, Lux-Lantos V, Rodriguez H, Cao G, Randi A, Cocca C, Núñez in the number of lobar buds (lobules). Animals dosed at 1 M. mg/kg/day had an increased incidence of hyperplastic mammary ducts cf. controls (45.6 ± 7.1% vs. 35.1 ± 8.5%, Endocrine disruptors (EDs) are compounds that interfere with hormone regulation and influence respectively, p < 0.05). A significantly higher incidence of mammary carcinogenesis. We have previously demonstrated that the pesticide chlorpyrifos (CPF) florid duct hyperplasias were present in animals dosed at ≥ acts as an ED in vitro, since it induces human breast cancer cells proliferation through estrogen 0.01 mg/kg/day cf. the control group. Animals dosed at 0.01 receptor alpha (ERα) pathway. In this work, we studied the effects of CPF at environmental doses mg/kg bw/day had a significantly (p < 0.05) increased (0.01 and 1mg/kg/day) on mammary gland, steroid hormone receptors expression and serum steroid incidence of lobular adenosis cf. controls; however no such hormone levels. It was carried out using female Sprague-Dawley 40-days-old rats exposed to the changes occurred in the high dose group (ie the finding was pesticide during 100 days. We observed a proliferating ductal network with a higher number of ducts not dose related). Animals dosed at 1 mg/kg bw/day had and alveolar structures. We also found an increased number of benign breast diseases, such as lower serum estracceptable daily intakeol, progesterone and hyperplasia and adenosis. CPF enhanced progesterone receptor (PgR) along with the proliferating testosterone levels cf. controls (p < 0.05). Serum LH levels cell nuclear antigen (PCNA) in epithelial ductal cells. On the other hand, the pesticide reduced the were significantly (p < 0.05) reduced cf. controls following APPENDIX 2 109
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expression of co-repressors of estrogen receptor activity REA and SMRT and it decreased serum dosing at ≥ 0.01 mg/kg bw/day. No effects on serum FSH estracceptable daily intakeol (E2), progesterone (Pg) and luteinizing hormone (LH) levels. Finally, levels were detected. Dosing at 0.01 mg/kg bw/day (but not we found a persistent decrease in LH levels among ovariectomized rats exposed to CPF. Therefore, at higher doses ie a dose response was not detected) CPF alters the endocrine balance acting as an ED in vivo. These findings warn about the harmful resulted in reduced nuclear receptor co-repressor 2 protein effects that CPF exerts on mammary gland, suggesting that this compound may act as a risk factor expression in mammary gland. for breast cancer. Overall the study provides some limited evidence of possible endocrine effects in rats. However, consistent dose responses and a biologically coherent pattern of events was not fully established by this study. No historical control data was provided for any of the measurements performed. Furthermore the statistical power of the study was very limited (n =6). Thus the results of this study are not consistent with the available high quality regulatory data. Further confirmatory data is required in order for this study to be of regulatory value.
51 J Steroid Biochem Mol Biol. 2018 Oct 2. pii: S0960-0760(18)30187-0. doi: The statistical power of this study (n = 6) is considered to be 10.1016/j.jsbmb.2018.09.021. [Epub ahead of print] inadequate. The minimum n for a study of this type is 50 females/dose at the commencement of the study with at least Effects of the pesticide chlorpyrifos on breast cancer disease. Implication of epigenetic 20 animals survival to study completion. The study is not mechanisms. regarded as being of regulatory value. Ventura C, Zappia CD, Lasagna M, Pavicic W, Richard S, Bolzan AD, Monczor F, Núñez M, Cocca C. Chlorpyrifos (CPF) is an organophosphorus pesticide used for agricultural pest control all over the world. We have previously demonstrated that environmental concentrations of this pesticide alter mammary gland histological structure and hormonal balance in rats chronically exposed. In this work, we analyzed the effects of CPF on mammary tumors development. Our results demonstrated that CPF increases tumor incidence and reduces latency of NMU-induced mammary tumors. Although no changes were observed in tumor growth rate, we found a reduced steroid hormone receptor expression in the tumors of animals exposed to the pesticide. Moreover, we analyzed the role of epigenetic mechanisms in CPF effects. Our results indicated that CPF alters HDAC1 mRNA expression in mammary gland, although no changes were observed in DNA methylation. In 110 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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summary, we demonstrate that the exposure to CPF promotes mammary tumors development with a reduced steroid receptors expression. It has also been found that CPF affects HDAC1 mRNA levels in mammary tissue pointing that CPF may act as a breast cancer risk factor.
52 Toxicology. 2018 Dec 1; 410:106–15. doi: 10.1016/j.tox.2018.09.008. Epub 2018 Sep 17. CPF was dissolved in DMSO to provide consistent absorption and was injected subcutaneously in a volume of 1 mL/kg Evaluation of the effects of chlorpyrifos combined with lipopolysaccharide stress on body weight at a dose of 2.5 mg/kg given daily at PND 11– neuroinflammation and spatial memory in neonatal rats. 14. The route of exposure is of limited regulatory relevance. Wang P, Dai H, Zhang C, Tian J, Deng Y, Zhao M, Zhao M, Bing G, Zhao L. The dose and likely systemic exposure far exceeds the NOEL for inhibition of blood cholinesterases in rats. The study Chlorpyrifos (CPF) may weaken the immune defenses of children, making them vulnerable to provides no additional useful data on low dose chlorpyrifos opportunistic bacterial infection. CPF combined with bacterial infection is a potential problem for effects. children during their childhood development. However, there is a lack of studies on the joint effects of these two factors on children. Here, we assessed the effects of CPF combined with lipopolysaccharide (LPS) on the inflammation and development of the nervous system. In this study, the cell toxicity of CPF plus LPS in cultured astrocytes, and the pathogenic effects of CPF plus LPS in neonatal rat models were observed. The hydrogen (H2)-inhalation was used for treatment to explore its therapeutic potential. We found that CPF plus LPS activated the astrocyte, which increased the expressions of HMGB1, TLR4, and p-NF-κB p65, while H2-inhalation reduced the expressions (p < 0.05). We also found that CPF plus LPS induced long-lasting spatial memory deficits throughout brain maturation. However, H2-inhalation improved rat performance in these behavioural experiments (p < 0.05). In conclusion, the sub-toxic concentration of CPF did not cause a significant damage in short term, but induced a severe long-term damage to the brain when combined with LPS. H2-inhalation reduced the neuronal damage and behavioural abnormalities caused by CPF and LPS exposure.
53 Environ Toxicol. 2017 Jul; 32(7):1927–36. doi: 10.1002/tox.22415. Epub 2017 Mar 15. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Cadmium and chlorpyrifos inhibit cellular immune response in spleen of rats. additional useful data on low dose chlorpyrifos effects. Wang P, Wang J, Sun YJ, Yang L, Wu YJ. Cadmium (Cd) and chlorpyrifos (CPF) are common pollutants coexisting in the environment, and both of them have been reported to have immunotoxicity to organisms. However, the joint effects of these two chemicals on the immune system are still unknown. In this study, we used CdCl2 and APPENDIX 2 111
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CPF to study their combined effects on immune functions in the spleen of rats. In in vivo experiments, SD rats were exposed to different doses of CdCl2 (0.7 and 6 mg kg-1 body weight/day) and CPF (1.7 and 15 mg kg-1 body weight/day) or their combinations for consecutive 28 days. The proliferation and cytokine production ability of the splenocytes isolated from the treated animals were assessed. In in vitro experiments, we used different concentrations of CdCl2 and CPF to treat concanavalin A (Con A)-induced splenocytes isolated from untreated rats. We found that the combination of CPF and high dose of CdCl2 had a synergistic inhibitory effect on production of IFN- γ by spleen cells induced by Con A. The in vitro results showed that two chemicals had different effects on the cell proliferation and cytokine production depending on the exposure doses and time. This result suggests that exposure to both CdCl2 and CPF at the environmentally-relevant low dose may be potentially more hazardous than exposure to each individual toxicant.
54 Chem Res Toxicol. 2015 Jun 15; 28(6):1216–23. doi: 10.1021/acs.chemrestox.5b00054. Epub 2015 Chlorpyrifos dose used exceeds the in vivo NOAELs for Apr 22. cholinesterase inhibition in rats. The study provides no additional useful data on low dose chlorpyrifos effects. Metabolomics analysis and biomarker identification for brains of rats exposed subchronically to the mixtures of low-dose cadmium and chlorpyrifos. Xu MY, Sun YJ, Wang P, Xu HY, Chen LP, Zhu L, Wu YJ. Cadmium (Cd) and chlorpyrifos (CPF) are widespread harmful environmental pollutants with neurotoxicity to mammals. Although the exposure to Cd and CPF at the same time may pose a significant risk to human health, the subchronic combined neurotoxicity of these two chemicals at low levels in the brain is poorly understood. In this study, we treated rats with three doses (low, middle, and high) of Cd, CPF, or their mixture for 90 days. No obvious symptom was observed in the treated animals except those treated with high-dose CPF. Histological results showed that middle and high doses of the chemicals caused neuronal cell damage in brains. GC-MS-based metabolomics analysis revealed that energy and amino acid metabolism were disturbed in the brains of rats exposed to the two chemicals and their combinations even at low doses. We further identified the unique brain metabolite biomarkers for rats treated with Cd, CPF, or both. Two amino acids, tyrosine and l-leucine, were identified as the biomarkers for Cd and CPF treatment, respectively. In addition, a set of five unique biomarkers (1,2-propanediol-1-phosphate, d-gluconic acid, 9H-purine, serine, and 2-ketoisovaleric acid) was identified for the mixtures of Cd and CPF. Therefore, the metabolomics analysis is more sensitive than regular clinical observation and pathological examination for detecting the neurotoxicity of the individual and combined Cd and CPF 112 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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at low levels. Overall, these results identified the unique biomarkers for Cd and CPF exposure, which provide new insights into the mechanism of their joint toxicity.
55 Toxicology. 2017 Jun 1; 384:50–58. doi: 10.1016/j.tox.2017.04.008. Epub 2017 Apr 19. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Metabolomic analysis for combined hepatotoxicity of chlorpyrifos and cadmium in rats. additional useful data on low dose chlorpyrifos effects. Xu MY, Wang P, Sun YJ, Wu YJ. Pesticides and heavy metals are widespread environmental pollutants. Although the acute toxicity of organophosphorus pesticide chlorpyrifos (CPF) and toxic heavy metal cadmium (Cd) is well characterized, the combined toxicity of CPF and Cd, especially the hepatotoxicity of the two chemicals with long-term exposure at a low dose, remained unclear. In this study, we investigated the toxicity in the liver of rats upon subchronic exposure to CPF and Cd at environmentally relevant doses. Rats were given three different doses (1/135 LD50, 1/45 LD50 and 1/15 LD50) of CPF and Cd as well as their mixtures by oral gavage for 90days. After treatment, the liver tissues were subjected to histopathological examination and biochemical analysis. Gas chromatography-mass spectrometry (GC-MS) was used to analyze the metabolomic changes in the rat liver upon CPF, Cd and their mixtures treatment. The results showed that CPF and Cd-induced oxidative damage and disrupted energy, amino acid, and fatty acid metabolism in the liver. Eleven biomarkers in liver were identified for CPF-, Cd-, and their mixture-treated rats. Three metabolites, ie butanedioic acid, myo- inositol, and urea, were identified as unique biomarkers for the mixture-treated rats. Moreover, we found that Cd could accelerate the metabolism of CPF in the liver when given together to the rats, which may lead to the potential antagonistic interaction between CPF and Cd. In conclusion, our results indicated that even at environmentally relevant doses, CPF and Cd could disrupt the liver metabolism. In addition, the accelerated metabolism of CPF by Cd may lead to their potential antagonistic interaction.
56 Toxicology. 2017 Jun 1; 384:50–58. doi: 10.1016/j.tox.2017.04.008. Epub 2017 Apr 19. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Metabolomic analysis for combined hepatotoxicity of chlorpyrifos and cadmium in rats. additional useful data on low dose chlorpyrifos effects. Xu MY, Wang P, Sun YJ, Wu YJ. Pesticides and heavy metals are widespread environmental pollutants. Although the acute toxicity of organophosphorus pesticide chlorpyrifos (CPF) and toxic heavy metal cadmium (Cd) is well APPENDIX 2 113
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characterized, the combined toxicity of CPF and Cd, especially the hepatotoxicity of the two chemicals with long-term exposure at a low dose, remained unclear. In this study, we investigated the toxicity in the liver of rats upon subchronic exposure to CPF and Cd at environmentally relevant doses. Rats were given three different doses (1/135 LD50, 1/45 LD50 and 1/15 LD50) of CPF and Cd as well as their mixtures by oral gavage for 90days. After treatment, the liver tissues were subjected to histopathological examination and biochemical analysis. Gas chromatography-mass spectrometry (GC-MS) was used to analyze the metabolomic changes in the rat liver upon CPF, Cd and their mixtures treatment. The results showed that CPF and Cd-induced oxidative damage and disrupted energy, amino acid, and fatty acid metabolism in the liver. Eleven biomarkers in liver were identified for CPF-, Cd-, and their mixture-treated rats. Three metabolites, ie, butanedioic acid, myo- inositol, and urea, were identified as unique biomarkers for the mixture-treated rats. Moreover, we found that Cd could accelerate the metabolism of CPF in the liver when given together to the rats, which may lead to the potential antagonistic interaction between CPF and Cd. In conclusion, our results indicated that even at environmentally relevant doses, CPF and Cd could disrupt the liver metabolism. In addition, the accelerated metabolism of CPF by Cd may lead to their potential antagonistic interaction.
57 Food Chem Toxicol. 2017 May; 103:246–52. doi: 10.1016/j.fct.2017.03.013. Epub 2017 Mar 9. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Joint toxicity of chlorpyrifos and cadmium on the oxidative stress and mitochondrial damage in additional useful data on low dose chlorpyrifos effects. neuronal cells. Xu MY, Wang P, Sun YJ, Yang L, Wu YJ. Pesticides and heavy metals can be easily biomagnified in food chains and bioaccumulated in individuals, thus pose significant threat to human health. However, their joint toxicity for long-term exposure at low dose has not been thoroughly investigated. In the present study, we investigated the oxidative damages in brain of rats exposed subchronically to organophosphorus pesticide chlorpyrifos (CPF) and heavy metal cadmium (Cd), and their mixtures at the environmentally relevant doses. Rats were given different doses of CPF and Cd by oral gavage for three months. After treatment, brain tissues were subjected for biochemical analysis. Mitochondrial damage and reactive oxidative species were also measured in neuroblastoma SH-SY5Y cells treated with CPF, Cd and their mixtures. The results showed that CPF and Cd generated protein and lipid peroxidation, disturbed the total antioxidant capability, and altered mitochondria ultrastructure in the brain. Lipids and proteins were sensitive to the oxidative damage induced by CPF and Cd. CPF and 114 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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Cd decreased mitochondrial potential and induced reactive oxygen species in SH-SY5Y cells. However, the mixture did not display higher toxicity than the sum of that of the individual treatments. Thus, CPF and Cd could have a potential antagonistic interaction on the induction of oxidative stress.
58 Environ Sci Pollut Res Int. 2018 Jun; 25(16):15616–29. doi: 10.1007/s11356-018-1776-x. Epub Chlorpyrifos dose used exceeds the in vivo NOAELs for 2018 Mar 23. cholinesterase inhibition in rats. Furthermore the study was conducted at a dose that produced overt anticholinesterase- Assessment of neurohepatic DNA damage in male Sprague-Dawley rats exposed to induced acute neurotoxicity that likely included respiratory organophosphates and pyrethroid insecticides. compromise. The study provides no additional useful data on Yahia D, Ali MF. low dose chlorpyrifos effects. The current work was undertaken to test the genotoxic potential of chlorpyrifos (CPF), dimethoate, and lambda cyhalothrin (LCT) insecticides in rat brain and liver using the single cell gel electrophoresis (comet assay). Three groups of adult male Sprague-Dawley rats were exposed orally to one third LD50of CPF, dimethoate, or LCT for 24 and 48 h while the control group received corn oil. Serum samples were collected for estimation of malondialdehyde (MDA) and glutathione peroxidase (GPx); the brain and liver samples were used for comet assay and for histopathological examination. Results showed that signs of neurotoxicity appeared clinically as backward stretching of hind limb and splayed gait in dimethoate and LCT groups, respectively. CPF, LCT, and dimethoate induced oxidative stress indicated by increased MDA and decreased GPx levels. CPF and LCT caused severe DNA damage in the brain and liver at 24 and 48 h indicated by increased percentage of DNA in tail, tail length, tail moment, and olive tail moment. Dimethoate induced mild DNA damage in the brain and liver at 48 h. Histopathological changes were observed in the cerebrum, cerebellum, and liver of exposed rats. The results concluded that CPF, LCT, and dimethoate insecticides induced oxidative stress and DNA damage associated with histological changes in the brain and liver of exposed rats.
59 Environ Toxicol. 2017 Sep; 32(9):2191–202. doi: 10.1002/tox.22432. Epub 2017 Jun 1. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Protective effects of Ziziphora tenuior extract against chlorpyrifos induced liver and lung toxicity in additional useful data on low dose chlorpyrifos effects. rat: Mechanistic approaches in subchronic study. Yazdinezhad A, Abbasian M, Hojjat Hosseini S, Naserzadeh P, Agh-Atabay AH, Hosseini MJ. APPENDIX 2 115
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Chlorpyrifos (CPF) is one of the most widely used organophosphorus, which has spurred renewed interest. This study was conducted to investigate the protective effect of ziziphora tenuior extract against CPF-induced liver and lung toxicity. This study conducted 8-week rat sub-chronic toxicity study and then the effect of ziziphora tenuior extract in 3 different doses (40, 80, 160 mg/kg) was determined. We administrated maximum tolerated dose of CPF (6.75 mg/kg) by gavage for 8 weeks (5 times in week) to male rats. Rats were sacrificed 24 h after last dose and the biochemical analysis, which confirms involvement of oxidative stress in the pathogenesis of CPF toxicity in liver including increased in lipid peroxidation, protein carbonyl content, and ROS formation, glutathione depletion, decreased of antioxidant effect via frap oxidation and cytochrome c expulsion. In addition, pathological lesions confirm the dysfunction of the organs (liver and lung). In addition, using of ziziphora extract as an antioxidant is resulted in amelioration of oxidative stress marker in liver and lung damage. In conclusion, the current study revealed that CPF toxicity is related to oxidative stress and induction of cell death signaling and cotreatment with ziziphora extract is recommended in the routine therapy for the protection against CPF induced liver and lung tissue damage.
60 Toxicology. 2015 Oct 2; 336:17–25. doi: 10.1016/j.tox.2015.07.014. Epub 2015 Jul 26. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Neonatal chlorpyrifos exposure induces loss of dopaminergic neurons in young adult rats. additional useful data on low dose chlorpyrifos effects. Zhang J, Dai H, Deng Y, Tian J, Zhang C, Hu Z, Bing G, Zhao L. Increasing epidemiological and toxicological evidence suggests that pesticides and other environmental exposures may be associated with the development of Parkinson's disease (PD). Chlorpyrifos (CPF) is a widely used organophosphorous pesticide with developmental neurotoxicity. Its neurotoxicity, notably on the monoamine system, suggests that exposure of CPF may induce dopaminergic neuronal injury. We investigated whether neonatal exposure to CPF contributes to initiation and progression of dopaminergic neurotoxicity and explored the possible underlying mechanisms. The newborn rats were administrated 5 mg/kg CPF subcutaneously from postnatal day (PND) 11 to PND 14 daily. The effect of CPF on dopaminergic neurons, microglia, astrocyte, nuclear factor-κB (NF-κB) p. 65 and p. 38 mitogen-activated protein kinase (MAPK) signaling pathways was analyzed in the substantia nigra of rats at 12h, 24h, 72 h, 16d and 46 d after exposure. CPF-treated rats exhibited significant reduction of dopaminergic neurons at 16d and 46 d after exposure, and a significant increase in the expression of microglia and astrocytes in the substantia nigra after CPF exposure. Intense activation of NF-κB p. 65 and p. 38 MAPK inflammatory signaling pathways was observed. Our findings indicate that neonatal exposure to CPF may induce long-term dopaminergic 116 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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neuronal damage in the substantia nigra mediated by the activation of inflammatory response via NF-κB p. 65 and p. 38 MAPK pathways in the nigrostriatal system.
61 Chemosphere. 2016 Jun; 153:287–93. doi: 10.1016/j.chemosphere.2016.03.055. Epub 2016 Mar 26. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. The study provides no Effects of chlorpyrifos on the gut microbiome and urine metabolome in mouse (Mus musculus). additional useful data on low dose chlorpyrifos effects. Given Zhao Y, Zhang Y, Wang G, Han R, Xie X. chlorpyrifos’s mode of action and the importance of cholinergic signalling in the control of gut motility and other In this study, the toxic effects of clorpyrifos (CPF) on the gut microbiome and related urine gut functions, it is hardly surprising that neurotoxic doses of metabolome in mouse (Mus musculus) were investigated. Mice were exposed to a daily dose of 1 chlorpyrifos result in changes in gut microflora. mg kg(-1) bodyweight of CPF for 30 d. As a result, CPF significantly altered the gut microbiota composition in terms of the relative abundance of key microbes. Meanwhile, CPF exposure induced the alterations of urine metabolites related to the metabolism of amino acids, energy, short-chain fatty acids (SCFAs), phenyl derivatives and bile acids. High correlations were observed between perturbed gut microbiome and altered metabolic profiles. These perturbations finally resulted in intestinal inflammation and abnormal intestinal permeability, which were also confirm by the histologic changes in colon and remarkable increase of lipopolysaccharide (LPS) and diamine oxidase (DAO) in the serum of CPF-treated mice. Our findings will provide a new perspective to reveal the mechanism of CPF toxicity.
62 Neurotox Res. 2018 Feb; 33(2):247–58. doi: 10.1007/s12640-017-9823-9. Epub 2017 Oct 3. None of these studies are regarded as being of regulatory quality due to inadequacies of the statistical methods used, Developmental Exposure to Pesticides Alters Motor Activity and Coordination in Rats: Sex lack of blinding of the observer and/or other techniques to Differences and Underlying Mechanisms. reduce observer bias, lack of assay validation by Gómez-Giménez B, Felipo V, Cabrera-Pastor A, Agustí A, Hernández-Rabaza V, Llansola M. incorporation of appropriate control groups and lack of historical control data. Because of the unreliability of the It has been proposed that developmental exposure to pesticides contributes to increasing study a NOAEL was not established. prevalence of neurodevelopmental disorders in children, such as attention deficit with hyperactivity (ADHD) and to alterations in coordination skills. However, the mechanisms involved in these alterations remain unclear. We analyzed the effects on spontaneous motor activity and motor coordination of developmental exposure to a representative pesticide of each one of the four main chemical families: organophosphates (chlorpyrifos), carbamates (carbaryl), organochlorines (endosulfan), and pyrethroids (cypermethrin). Pesticides were administered once a day orally, in a sweet jelly, from gestational day 7 to post-natal day 21. Spontaneous motor activity was assessed APPENDIX 2 117
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by an actimeter and motor coordination using the rotarod, when rats were adults. The effects were analyzed separately in males and females. Extracellular GABA in cerebellum and NMDA receptor subunits in hippocampus were assessed as possible underlying mechanisms of motor alterations. Motor coordination was impaired by developmental exposure to endosulfan, cypermethrin, and chlorpyrifos in females but not in males. The effect of endosulfan and cypermethrin would be due to increased extracellular GABA in cerebellum, which remains unaltered in male rats. Chlorpyrifos increased motor activity in males and females. Cypermethrin decreased motor activity mainly in males. In male rats, but not in females, expression of the NR2B subunit of NMDA receptor in hippocampus correlated with motor activity. These results show sex-specific effects of different pesticides on motor activity and coordination, associated with neurotransmission alterations. These data contribute to better understand the relationship between developmental exposure to the main pesticide families and motor disorders in children.
63 Food Chem Toxicol. 2017 Jan; 99:135–48. doi: 10.1016/j.fct.2016.11.028. Epub 2016 Nov 29. None of these studies are regarded as being of regulatory quality due to inadequacies of the statistical methods used, Sex-dependent effects of developmental exposure to different pesticides on spatial learning. The lack of blinding of the observer and/or other techniques to role of induced neuroinflammation in the hippocampus. reduce observer bias, lack of assay validation by Gómez-Giménez B, Llansola M, Hernández-Rabaza V, Cabrera-Pastor A, Malaguarnera M, Agusti incorporation of appropriate control groups and lack of A, Felipo V. historical control data. Because of the unreliability of the study a NOAEL was not established. The use of pesticides has been associated with impaired neurodevelopment in children. The aims of this work were to assess: 1) the effects on spatial learning of developmental exposure to pesticides 2) if the effects are sex-dependent and 3) if hippocampal neuroinflammation is associated with the impairment of spatial learning. We analyzed the effects of developmental exposure to four pesticides: chlorpyrifos, carbaryl, endosulfan and cypermethrin. Exposure was from gestational day 7 to post-natal day 21 and spatial learning and memory was assessed when the rats were young adults. The effects of pesticides on spatial learning were pesticide and gender-dependent. Carbaryl did not affect spatial learning in males or females. Endosulfan and chlorpyrifos impaired learning in males but not in females. Cypermethrin improved spatial learning in the Morris water maze both in males and females while impaired learning in the racceptable daily intakeal maze only in males. Spatial learning ability was lower in control female rats than in males. All pesticides induced neuroinflammation, increasing IL-1b content in the hippocampus and there is a negative correlation 118 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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between IL-1b levels in the hippocampus and spatial learning. Neuroinflammation would contribute to the effects of pesticides on spatial learning.
64 Environ Health. 2018 Nov 16; 17(1):77. doi: 10.1186/s12940-018-0421-y. Safety of Safety Evaluation of Pesticides: developmental neurotoxicity of chlorpyrifos and chlorpyrifos-methyl. Mie A, Rudén C, Grandjean P. Authorization of pesticides for market release requires toxicity testing on animals, typically performed by test laboratories on contract with the pesticide producer. The latter provides the results and summary to the regulatory authorities. For the commonly used pesticide chlorpyrifos, an industry-funded toxicity study concludes that no selective effects on neurodevelopment occur even at high exposures. In contrast, the evidence from independent studies points to adverse effects of current exposures on cognitive development in children. We reviewed the industry-funded developmental neurotoxicity test data on chlorpyrifos and the related substance chlorpyrifos-methyl. We noted treatment-related changes in a brain dimension measure for chlorpyrifos at all dose levels tested, although not been reported in the original test summary. We further found issues which inappropriately decrease the ability of the studies to reveal true effects, including a dosage regimen that resulted in too low exposure of the nursing pups for chlorpyrifos and possibly for chlorpyrifos- methyl, and a failure to detect any neurobehavioural effects of lead nitrate used as positive control in the chlorpyrifos study. Our observations thus suggest that conclusions in test reports submitted by the producer may be misleacceptable daily intakeng. This discrepancy affects the ability of regulatory authorities to perform a valid and safe evaluation of these pesticides. The difference between raw data and conclusions in the test reports indicates a potential existence of bias that would require regulatory attention and possible resolution.
The claimed critical effect identified in this re-evaluation of one part of the chlorpyrifos developmental neurotoxicity regulatory study was an effect of cerebellum height in rat pups at post-natal day 11 of age following maternal dosing at APPENDIX 2 119
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≥ 0.3 mg/kg bw/day. Notably, this claimed effect occurred at a dose that exceeds the NOEL for inhibition of blood cholinesterases in rats.
Guinea Pig
65 Braz J Otorhinolaryngol. 2016 Jan-Feb; 82(1):11–6. doi: 10.1016/j.bjorl.2015.10.001. Epub 2015 Oct Chlorpyrifos dose used exceeds the in vivo NOAELs for 24. cholinesterase inhibition in rats. Since specific data on the NOAELs for cholinesterase inhibition in guinea pigs is Morphological analysis of the vestibular system of guinea pigs poisoned by organophosphate. limited, it is assumed on the basis of read across that the Cogo LA, Santos Filha VA, Murashima Ade A, Hyppolito MA, Silveira AF. relevant thresholds for guinea pigs are similar to those in rats. INTRODUCTION: The vestibular system is responsible for body balance. There are substances that damage it, causing dizziness; these are termed vestibulotoxic substances. Agrochemicals have been investigated for ototoxicity because of studies that identified dizziness as a recurrent symptom among rural workers' complaints. OBJECTIVE: To histopathologically evaluate the vestibular system in guinea pigs exposed to an organophosphate, and to identify the drug's effects on this system. METHODS: Experimental clinical study. Eighteen guinea pigs were used; six of them poisoned with the organophosphate chlorpyrifos at doses of 0.5mg/kg/day and seven of them at 1mg/kg/day; and a control group of five guinea pigs was exposed to distilled water, all for 10 consecutive days. Later, ciliary tufts of saccule and utricle maculae were counted by scanning electron microscopy. RESULTS: Comparing the groups, a one-way ANOVA test for the variable ‘saccule’ (p=0.0569) and a Kruskal-Wallis test for the variable "utricle" (p=0.8958) were performed, revealing no difference among groups in both variables. CONCLUSION: The histopathologic analysis of the vestibular system of guinea pigs exposed to an organophosphate showed no difference in the amount of ciliary tufts of saccule and utricle maculae at the doses tested, although the result for the variable "saccule" was considered borderline, showing a trend for significance.
66 Neurotoxicology. 2016 Sep; 56:17–28. doi: 10.1016/j.neuro.2016.06.008. Epub 2016 Jun 11. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. Since specific data on the Spatial learning impairment in prepubertal guinea pigs prenatally exposed to the organophosphorus NOAELs for cholinesterase inhibition in guinea pigs is pesticide chlorpyrifos: Toxicological implications. limited, it is assumed on the basis of read across that the 120 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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Mamczarz J, Pescrille JD, Gavrushenko L, Burke RD, Fawcett WP, DeTolla LJ Jr, Chen H, Pereira relevant thresholds for guinea pigs are similar to those in EFR, Albuquerque EX. rats. Exposure of the developing brain to chlorpyrifos (CPF), an organophosphorus (OP) pesticide used extensively in agriculture worldwide, has been associated with increased prevalence of cognitive deficits in children, particularly boys. The present study was designed to test the hypothesis that cognitive deficits induced by prenatal exposure to sub-acute doses of CPF can be reproduced in precocial small species. To address this hypothesis, pregnant guinea pigs were injected daily with CPF (25mg/kg,s.c.) or vehicle (peanut oil) for 10days starting on presumed gestation day (GD) 53- 55. Offspring were born around GD 65, weaned on postnatal day (PND) 20, and subjected to behavioural tests starting around PND 30. On the day of birth, butyrylcholinesterase (BuChE), an OP bioscavenger used as a biomarker of OP exposures, and acetylcholinesterase (AChE), a major molecular target of OP compounds, were significantly inhibited in the blood of CPF-exposed offspring. In their brains, BuChE, but not AChE, was significantly inhibited. Prenatal CPF exposure had no significant effect on locomotor activity or on locomotor habituation, a form of non-associative memory assessed in open fields. Spatial navigation in the Morris water maze (MWM) was found to be sexually dimorphic among guinea pigs, with males outperforming females. Prenatal CPF exposure impaired spatial learning more significantly among male than female guinea pigs and, consequently, reduced the sexual dimorphism of the task. The results presented here, which strongly support the test hypothesis, reveal that the guinea pig is a valuable animal model for preclinical assessment of the developmental neurotoxicity of OP pesticides. These findings are far reaching as they lay the groundwork for future studies aimed at identifying therapeutic interventions to treat and/or prevent the neurotoxic effects of CPF in the developing brain.
67 Neurotoxicology. 2015 May; 48:9–20. doi: 10.1016/j.neuro.2015.02.002. Epub 2015 Feb 19. Chlorpyrifos dose used exceeds the in vivo NOAELs for cholinesterase inhibition in rats. Since specific data on the Prenatal exposure of guinea pigs to the organophosphorus pesticide chlorpyrifos disrupts the NOAELs for cholinesterase inhibition in guinea pigs is structural and functional integrity of the brain. limited, it is assumed on the basis of read across that the Mullins RJ, Xu S, Pereira EF, Pescrille JD, Todd SW, Mamczarz J, Albuquerque EX, Gullapalli RP. relevant thresholds for guinea pigs are similar to those in rats. This study was designed to test the hypothesis that prenatal exposure of guinea pigs to the organophosphorus (OP) pesticide chlorpyrifos (CPF) disrupts the structural and functional integrity of the brain. Pregnant guinea pigs were injected with chlorpyrifos (25 mg/kg, s.c.) or vehicle (peanut oil) once per day for 10 consecutive days, starting approximately on the 50th day of gestation. APPENDIX 2 121
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Cognitive behaviour of female offspring was examined starting at 40–45 post-natal days (PND) using the Morris water maze (MWM), and brain structural integrity was analyzed at PND 70 using magnetic resonance imaging (MRI) methods, including T2-weighted anatomical scans and diffusion kurtosis imaging (DKI). The offspring of exposed mothers had significantly decreased body weight and brain volume, particularly in the frontal regions of the brain including the striatum. Furthermore, the offspring demonstrated significant spatial learning deficits in MWM recall compared to the vehicle group. Diffusion measures revealed reduced white matter integrity within the striatum and amygdala that correlated with spatial learning performance. These findings reveal the lasting effect of prenatal exposure to CPF as well as the danger of mother to child transmission of CPF in the environment.
Human
68 Ann Agric Environ Med. 2015; 22(2):275–80. doi: 10.5604/12321966.1152080. The dosimetry method used was dependent on back calculating estimated absorbed daily dose based upon the A new method for setting guidelines to protect human health from agricultural exposure by using creatinine corrected (based on the individual daily creatinine chlorpyrifos as an example. excretion rate (g/d) calculated ‘typical’ population values Phung DT, Connell D, Chu C. based on age, gender, height and weight of the exposed individual) of concentration of the chlorpyrifos metabolite INTRODUCTION AND OBJECTIVES: Guidelines set by various agencies for the control and TCPy in urine. The limitation of this approach is that while management of chlorpyrifos cover a wide range of values reflecting difficulties in the procedures for TCPy excretion in urine dose increase with increasing their development. To overcome these difficulties a new method to set guidelines would be exposure (ie the two variables are statistically significantly developed. Published data derived from epidemiological investigations on human populations would correlated p < 0.05), the correlation coefficient (r; Pearson be used to develop a dose-response relationship for chlorpyrifos allowing the calculation of product-moment correlation coefficient) between the two threshold values which can be used as guidelines. MATERIALS AND METHOD: Data from the variables is fairly low (typically ≈ 0.6).3 Furthermore, the scientific literature on human populations were collected to evaluate the adverse response doses for validity of the metric is based on the reliability of using a range of health effects. The Cumulative Frequency Distribution (CFD) for the minimum levels of ‘typical’ population means for daily creatinine excretion. adverse effects measured in terms of the Lifetime Average Daily Dose (LADD(D)) and the Absorbed There are many factors that influence such typical population Daily Dose for neurological (ADD(DN)) and non-neurological effects were used. RESULTS: Linear regression equations were fitted to the CFD plots giving R 2 values of 0.93 and 0.86 indicating a
3Burns CJ, Garabrant D, Albers JW, Berent S, Giordani B, Haidar S, Garrison R, Richardson RJ. Chlorpyrifos exposure and biolog ical monitoring among manufacturing workers. Occup Environ Med. 2006 Mar; 63(3):218-20. PubMed PMID: 16497866; PubMed Central PMCID: PMC2078143. 122 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE
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normal distribution of the data. Using these CFD plots, the chronic and acute threshold values were values and no attempt was made to account for the variance calculated at the 5% cumulative frequency level for chlorpyrifos exposure giving values at of such measures across the human population(s) of interest. 0.5 µg/kg/d and 3 µg/kg/d respectively. Thus while this approach provides useful supporting CONCLUSIONS: Guidelines set using this technique at the values at 0.5 µg/kg/d and 3 µg/kg/d for information for the derivation of human health based chronic and acute exposure respectively provide an alternative to the currently used biological guidance values, it is only sufficiently accurate for derivation endpoint and safety factor method. of semi-quantitative exposure estimates (eg distinguishing between low, medium and high exposures). However, this approach does provide some degree of support for the proposed updated APVMA acceptable daily intake and ArfD values for chlorpyrifos that are presented in this report.
69 & 70 Cortex. 2016 Jan; 74:383–95. doi: 10.1016/j.cortex.2015.09.011. Epub 2015 Oct 20. The studies evaluated male adolescent (12–21 years old) chlorpyrifos applicators. The level of chlorpyrifos exposure in A 10-month prospective study of organophosphorus pesticide exposure and neurobehavioural the high exposure cohort was very high over the 25 day performance among adolescents in Egypt. chlorpyrifos application period with above the low exposure Rohlman DS, Ismail AA, Rasoul GA, Bonner MR, Hendy O, Mara K, Wang K, Olson JR. cohort exposure for > 200 days. Applicators in the high exposure group reported working for the Ministry of Chlorpyrifos is an organophosphorus (OP) pesticide widely used around the world for agricultural Agriculture an average of 22 h per week. operations. Although studies have examined exposure in children, there is limited information on adolescents who are occupationally exposed. Furthermore, there is limited research addressing the The majority of neurobehavioural summary measures, 18 out change in exposure patterns and outcomes across the application season. The goal of the current of 22, indicated worse performance for the high exposure study was to examine the impact of chlorpyrifos exposure on neurobehavioural performance in group compared to the low exposure group. adolescents before, during and after the application season. The longitudinal study was conducted Many of the workers evaluated in these studies had levels of in Egypt from April 2010 to January 2011, quantifying exposure and neurobehavioural performance chlorpyrifos exposure associated with inhibition of blood with repeated measures prior to, during, and following the application period. At each test session, cholinesterases. Accordingly the studies do not provide participants completed a neurobehavioural test battery and urine was collected for analysis of the useful information on possible neurological effects at chlorpyrifos metabolite 3,5,6-trichloro-2 pyridinol (TCP ) (biomarker of exposure). Cumulative y exposures below those that inhibit blood cholinesterases. urinary TCPy over the study period was used to classify participants into low ( Summary Study and published abstract Study evaluation No. exposure group compared with the low exposure group. Additionally, changes in neurobehavioural performance across the application season indicate a pattern of impaired performance in the high exposure group compared to the low exposure group. Deficits increased during the application season and remained even months after application ceased. This study is the first to examine the impact of changes in pesticide exposure and neurobehavioural performance not only before and after the application season, but also within the application season. Furthermore, this study examines the impact of pesticide exposure on an adolescent population who may be at greater risk than adult populations. Int J Hyg Environ Health. 2015 Mar; 218(2):203–11. doi: 10.1016/j.ijheh.2014.10.005. Epub 2014 Nov 7. Longitudinal assessment of occupational exposures to the organophosphorous insecticides chlorpyrifos and profenofos in Egyptian cotton field workers. Singleton ST, Lein PJ, Dadson OA, McGarrigle BP, Farahat FM, Farahat T, Bonner MR, Fenske RA, Galvin K, Lasarev MR, Anger WK, Rohlman DS, Olson JR. Chlorpyrifos (CPF) and profenofos (PFF) are organophosphorus (OP) insecticides that are applied seasonally in Egypt to cotton fields. Urinary trichloro-2-pyridinol (TCPy), a specific CPF metabolite, and 4-bromo-2-chlorophenol (BCP), a specific PFF metabolite, are biomarkers of exposure, while inhibition of blood butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) activities are effect biomarkers that may be associated with neurotoxicity. Urinary TCP y and BCP and blood BChE and AChE activities were measured in 37 adult Egyptian Ministry of Agriculture workers during and after 9–17 consecutive days of CPF application followed by an application of PFF (9–11 days), and a second CPF application (5 days) in 2008. During the OP applications, urinary TCP y and BCP levels were significantly higher than baseline levels, remained elevated following the application periods, and were associated with an exposure related inhibition of blood BChE and Ache. Analysis of blood AChE levels before and after the PFF application period suggests that individual workers with peak BCP levels greater than 1000 μg/g creatinine exhibited further inhibition of blood AChE with PFF application, demonstrating that PFF exposure had a negative impact on AChE activity in this highly exposed worker population. While large interindividual differences in exposure were observed throughout this longitudinal study (peak urinary BCP and peak TCP y levels for individuals ranging from 13.4 to 8052 and 16.4 to 30,107 μg/g creatinine, respectively), these urinary biomarkers were highly correlated within workers (r=0.75, p<0.001). This suggests that the relative 124 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE Summary Study and published abstract Study evaluation No. exposures to CPF and PFF were highly correlated for a given worker. The variable exposures between job classification and work site suggest that job title and work location should not be used as the sole basis for categorizing OP exposures when assessing neurobehavioural and other health outcomes in Egyptian cotton field workers. Together, these findings will be important in educating the Egyptian insecticide application workers in order to encourage the development and implementation of work practices and personal protective equipment to reduce their exposure to CPF and PFF. 71 Environ Health Perspect. 2017 Sep 8; 125(9):097007. doi: 10.1289/EHP604. Bystander pesticide exposure assessment: Exposure was based on California pesticide use reports (PURs). PUR data Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum measures pesticide uses down to 2.59 square km (1 square Disorder. mile) units (MTRS). This data was evaluated using a spatial Schmidt RJ, Kogan V, Shelton JF, Delwiche L, Hansen RL, Ozonoff S, Ma CC, McCanlies EC, model, for each day, circular buffers were drawn around each Bennett DH, Hertz-Picciotto I, Tancredi DJ, Volk HE. home with racceptable daily intakei of 1,250, 1,500, and 1750 m. If the buffer intersected the centroid (centermost point) of BACKGROUND: Maternal folic acid (FA) protects against developmental toxicity from certain an MTRS where pesticides had been applied, the type and environmental chemicals. OBJECTIVE: We examined combined exposures to maternal FA and amount were linked to the home as a proximal exposure. This pesticides in relation to autism spectrum disorder (ASD). METHODS: Participants were California model generated an exposure profile by day of pregnancy. All children born from 2000–07 who were enrolled in the Childhood Autism Risks from Genetics and the records with no exposure identified were assigned to zero Environment (CHARGE) case-control study at age 2–5 y, were clinically confirmed to have ASD pounds applied. The daily exposure profile was then (n=296) or typical development (n=220), and had information on maternal supplemental FA and aggregated into time periods of interest for analysis, such as pesticide exposures. Maternal supplemental FA and household pesticide product use were months and trimesters; for this study, we used the six-mo retrospectively collected in telephone interviews from 2003–11. High vs. low daily FA intake was period beginning three mo before conception through the end dichotomized at 800μg (median). Mothers' addresses were linked to a statewide database of of the third month of pregnancy (end of the first trimester). commercial applications to estimate agricultural pesticide exposure. RESULTS: High FA intake Exposure over the entire pregnancy period was also (≥800μg) during the first pregnancy month and no known pesticide exposure was the reference assessed. group for all analyses. Compared with this group, ASD was increased in association with <800μg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, Occupational pesticide exposure: exposure assessment was 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, qualitative only (code of 0 (none), 1 (exposure above 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) to pet background levels; no more than a few days per year), 2 pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, (most likely exposed; exposure was unlikely to be daily), or 3 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or (definitely exposed; frequent or routine exposure) was after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. APPENDIX 2 125 Summary Study and published abstract Study evaluation No. Except for carbamates, these ORs were approximately two times greater than those for either entered to estimate both the frequency and intensity for each exposure alone or for the expected ORs for combined exposures under multiplicative or additive of the agents of interest). models. CONCLUSIONS: In this study population, associations between pesticide exposures and While the study results are noted, the exposure assessment ASD were attenuated among those with high versus low FA intake during the first month of was insufficiently quantitative to be of use for setting human pregnancy. Confirmatory and mechanistic studies are needed. https://doi.org/10.1289/EHP604. health based guidance values for chlorpyrifos. 126 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE Summary Study and published abstract Study evaluation No. 72 & 73 Environ Int. 2017 Sep; 106:248–56. doi: 10.1016/j.envint.2017.05.015. Epub 2017 Jun 8. The concentration of chlorpyrifos in placental cord blood plasma samples that was detected in this study was very Prenatal naled and chlorpyrifos exposure is associated with deficits in infant motor function in a high (shown as ng/mL = µg/L): cohort of Chinese infants. Silver MK, Shao J, Zhu B, Chen M, Xia Y, Kaciroti N, Lozoff B, Meeker JD. Comment in: Environ Int. 2018 May; 114:50–51. BACKGROUND: Organophosphate insecticides (OPs) are used worldwide, yet despite nearly ubiquitous exposure in the general population, few have been studied outside the laboratory. Fetal Notably, the 90th percentile chord blood plasma concentration brains undergo rapid growth and development, leaving them susceptible to long-term effects of for chlorpyrifos (1.92 ng/mL) is several orders of magnitude neurotoxic OPs. The objective here was to investigate the extent to which prenatal exposure to OPs higher than the maximums reported in the U.S. (0.002–0.065 affects infant motor development. METHODS: 30 OPs were measured in umbilical cord blood using ng/mL). For comparison, the Columbia Childrens gas chromatography tandem mass spectrometry in a cohort of Chinese infants. Motor function was Environmental Health Study identified chlorpyrifos at a assessed at 6-weeks and 9-months using Peabody Developmental Motor Scales 2nd edition (PDMS- concentration of 9 pg/g in pooled blood samples. 2) (n=199). Outcomes included subtest scores: reflexes, stationary, locomotion, grasping, visual- Furthermore, In a human volunteer study involving a single motor integration (V-M), composite scores: gross (GM), fine (FM), total motor (TM), and oral dose of 0.5 mg/kg bw, peak blood chlorpyrifos levels standardized motor quotients: gross (GMQ), fine (FMQ), total motor (TMQ). RESULTS: Naled, were less than 30 ng/ml, and represented only a fraction of 4 methamidophos, trichlorfon, chlorpyrifos, and phorate were detected in ≥10% of samples. Prenatal the levels of TCPy. Detectable inhibition of plasma naled and chlorpyrifos were associated with decreased 9-month motor function. Scores were 0.55, cholinesterase occurred at this does level. 0.85, and 0.90 points lower per 1ng/mL increase in log-naled, for V-M (p=0.04), FM (p=0.04), and FMQ (p=0.08), respectively. For chlorpyrifos, scores were 0.50, 1.98, 0.80, 1.91, 3.49, 2.71, 6.29, Assuming that the study’s analytical work is correct (see 2.56, 2.04, and 2.59 points lower for exposed versus unexposed infants, for reflexes (p=0.04), comments below), the data implies very high levels of locomotion (p=0.02), grasping (p=0.05), V-M (p<0.001), GM (p=0.007), FM (p=0.002), TM exposure to chlorpyrifos in the studied individuals ie (p<0.001), GMQ (p=0.01), FMQ (p=0.07), and TMQ (p=0.008), respectively. Girls appeared to be exposure levels potentially well above those that inhibit blood more sensitive to the negative effects of OPs on 9-month motor function than boys. cholinesterases. CONCLUSIONS: We found deficits in 9-month motor function in infants with prenatal exposure to However there are a number of valid methodological naled and chlorpyrifos. Naled is being aerially sprayed to combat mosquitoes carrying Zika virus, concerns with the analytical work carried out in this study: (a) yet this is the first non-occupational human study of its health effects. Delays in early-motor skill the validation of the assay was performed using serum not acquisition may be detrimental for downstream development and cognition. plasma samples; (b) the assay quality control samples were generated using serum samples not plasma samples; (c) 4Nolan, R.J., Rick, D.L., Freshour, N.L., and Saunders, J.H. (1984). Chlorpyrifos: Pharmacokinetics in human volunteers. Toxicol. Appl. Pharmacol. 73:8–15. APPENDIX 2 127 Summary Study and published abstract Study evaluation No. Int J Hyg Environ Health. 2018 Apr; 221(3):469–78. doi: 10.1016/j.ijheh.2018.01.010. there was prolonged storage of the samples without the appropriate stability and validation data that is required for Prenatal organophosphate insecticide exposure and infant sensory function. such a procedure; (d) there is a lack of appropriate recovery Silver MK, Shao J, Ji C, Zhu B, Xu L, Li M, Chen M, Xia Y, Kaciroti N, Lozoff B, Meeker JD. data with the analysis (for comparison, the Columbia Children’s Environmental Health study provided excellent BACKGROUND: Occupational studies suggest that exposure to organophosphate insecticides quality control data that ensured confidence in the analytical (OPs) can lead to vision or hearing loss. Yet the effects of early-life exposure on visual and auditory data even though extraction efficiency of chlorpyrifos from function are unknown. Here we examined associations between prenatal OP exposure and grating the blood was relatively low,∼18%, the sensitivity of the visual acuity (VA) and auditory brainstem response (ABR) during infancy. METHODS: 30 OPs were analysis plus the incorporation of deuterated internal measured in umbilical cord blood using gas chromatography tandem mass spectrometry in a cohort standards allowed for reliable estimates). of Chinese infants. Grating visual acuity (VA) (n = 179–200) and auditory brainstem response (ABR) (n = 139–183) were assessed at 6 weeks, 9 months, and 18 months. Outcomes included VA score, There are also other methodological concerns, most notable ABR wave V latency and central conduction time, and head circumference (HC). Associations of which are: (a) that the primary purpose of the study was as between sensory outcomes during infancy and cord OPs were examined using linear mixed models. a longitudinal study of iron deficiency and infant RESULTS: Prenatal chlorpyrifos exposure was associated with lower 9-month grating VA scores; neurodevelopment; (b) only 237 out of 359 participants had scores were 0.64 (95% CI: -1.22, -0.06) points lower for exposed versus unexposed infants sufficient cord blood for pesticide analysis; and (c) of the 237 (p = 0.03). The OPs examined were not associated with infant ABR latencies, but chlorpyrifos and participants with sufficient sample size 19.3% had low cord phorate were both significantly inversely associated with HC at 9 months; HCs were 0.41 (95% CI: ferritin. 0.75, 0.6) cm and 0.44 (95% CI: 0.88, 0.1) cm smaller for chlorpyrifos (p = 0.02) and phorate Importantly, given that the initial elimination rate of (p = 0.04), respectively. CONCLUSIONS: We found deficits in grating VA and HC in 9-month-old chlorpyrifos from plasma is very rapid (plasma half-life of infants with prenatal exposure to chlorpyrifos. The clinical significance of these small but statistically chlorpyrifos is very short on the order of 1 h or less), it is significant deficits is unclear. However, the disruption of visual or auditory pathway maturation in likely that the levels of chlorpyrifos detected in maternal and infancy could potentially negatively affect downstream cognitive development. cord blood at the time of delivery are reflective of a ‘steady- state’ value that is greatly influenced by an equilibrium between acceptable daily intakepose tissue and blood lipids. However, little is known about the terminal half-life of chlorpyrifos after steady state is achieved following repeated, relatively low-level exposure. If the terminal half-life was measured in months, then the values collected at the time of delivery could be reasonable indicators of the levels of exposure throughout pregnancy. Conversely, if the terminal half-life was measured in days, then the values obtained at the time of delivery might have little relationship to exposure levels that were present during most the pregnancy. Thus, it 128 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE Summary Study and published abstract Study evaluation No. is unclear whether this single measurement of chlorpyrifos in plasma, collected at the time of delivery, provides a relevant measure of chlorpyrifos exposure during the period of prenatal central nervous system (CNS) development (last 3– 4 months of pregnancy). Because of its multiple limitations, the results of these studies (particularly the analytical results) are not regarded as being reliable. Furthermore, if the blood analytical results are correct, the level of exposure likely resulted in inhibition of blood cholinesterases. 74 Int J Hyg Environ Health. 2015 Mar; 2 18(2):203–11. doi: 10.1016/j.ijheh.2014.10.005. Epub 2014 The results of this study indicate that worker exposure Nov 7. resulted in inhibition of blood cholinesterases ie the exposure likely exceeded the Australian health based guidance values. Longitudinal assessment of occupational exposures to the organophosphorous insecticides chlorpyrifos and profenofos in Egyptian cotton field workers. Singleton ST, Lein PJ, Dadson OA, McGarrigle BP, Farahat FM, Farahat T, Bonner MR, Fenske RA, Galvin K, Lasarev MR, Anger WK, Rohlman DS, Olson JR. Chlorpyrifos (CPF) and profenofos (PFF) are organophosphorus (OP) insecticides that are applied seasonally in Egypt to cotton fields. Urinary trichloro-2-pyridinol (TCPy), a specific CPF metabolite, and 4-bromo-2-chlorophenol (BCP), a specific PFF metabolite, are biomarkers of exposure, while inhibition of blood butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) activities are effect biomarkers that may be associated with neurotoxicity. Urinary TCP y and BCP and blood BChE and AChE activities were measured in 37 adult Egyptian Ministry of Agriculture workers during and after 9–17 consecutive days of CPF application followed by an application of PFF (9–11 days), and a second CPF application (5 days) in 2008. During the OP applications, urinary TCP y and BCP levels were significantly higher than baseline levels, remained elevated following the application periods, and were associated with an exposure related inhibition of blood BChE and Ache. Analysis of blood AChE levels before and after the PFF application period suggests that individual workers with peak BCP levels greater than 1000 μg/g creatinine exhibited further inhibition of blood AChE with PFF application, demonstrating that PFF exposure had a negative impact on AChE activity in APPENDIX 2 129 Summary Study and published abstract Study evaluation No. this highly exposed worker population. While large interindividual differences in exposure were observed throughout this longitudinal study (peak urinary BCP and peak TCP y levels for individuals ranging from 13.4 to 8052 and 16.4 to 30,107 μg/g creatinine, respectively), these urinary biomarkers were highly correlated within workers (r=0.75, p<0.001). This suggests that the relative exposures to CPF and PFF were highly correlated for a given worker. The variable exposures between job classification and work site suggest that job title and work location should not be used as the sole basis for categorizing OP exposures when assessing neurobehavioural and other health outcomes in Egyptian cotton field workers. Together, these findings will be important in educating the Egyptian insecticide application workers in order to encourage the development and implementation of work practices and personal protective equipment to reduce their exposure to CPF and PFF. 75 Environ Res. 2016 Aug; 149:164–70. doi: 10.1016/j.envres.2016.05.011. Epub 2016 May 18. The results of this study indicate that worker exposure very likely exceeded the Australian health based guidance values. Chlorpyrifos exposure in farmers and urban adults: Metabolic characteristic, exposure estimation, Importantly, the difficulties and inaccuracies in using urinary and potential effect of oxidative damage. TCPy values to back calculate likely chlorpyrifos exposure Wang L, Liu Z, Zhang J, Wu Y, Sun H. levels are discussed above. Such techniques are likely semi- quantitative at best, thus this study may tend to overestimate Chlorpyrifos is a widely used organophosphorus pesticide that efficiently protects crops against the accuracy of this approach. pests. However, recent studies suggest that severe exposure to chlorpyrifos may present adverse health effects in human. To analyze the exposure level and metabolic characteristics of chlorpyrifos pesticide in urban adults and farmers with/without occupation pesticide contact, the occurrence of urinary chlorpyrifos and methyl chlorpyrifos (CP-me), as well as their metabolite, 3,5,6-trichloro-2- pyridinol (TCPy), was determined in farmers of an agricultural village in China, and in urban adults of a nearby town. The geometric mean (GM) concentrations of TCPy, which is the major marker of chlorpyrifos exposure, were 4.29 and 7.57μg/g-creatinine in urban adults and farmers before pesticide application, respectively. Chlorpyrifos spraying significantly increased the concentrations of urinary TCPy. In the first day after spraying, a GM concentration of 43.7μg/g-creatinine was detected in the urine specimens from farmers, which decreased to 38.1 and 22.8μg/g-creatinine in the second and third day after chlorpyrifos spraying. The ratio of TCP y and its parent compounds, ie chlorpyrifos and CP-me, was positively associated with the sum concentration of urinary chlorpyrifos, CP-me, and TCPy, suggesting the increasing metabolic efficiency of chlorpyrifos to TCPy at higher chlorpyrifos exposure levels. To estimate the farmers' occupational exposure to chlorpyrifos pesticide, a new model based on the fitted first-order elimination kinetics of TCPy was 130 RECONSIDERATION OF CHLORPYRIFOS: 2019 TOXICOLOGY UPDATE Summary Study and published abstract Study evaluation No. established. Occupational chlorpyrifos exposure in a farmer was estimated to be 3.70μg/kg-bw/day (GM), which is an exposure level that is higher than the recommended guideline levels. Significant increase of urinary 8-hydroxydeoxyguanosine (8-OHdG) was observed on the first day after chlorpyrifos spraying, which indicates a potential oxidative damage in farmers. However, urinary 8- OHdG returned to its baseline level within two days. 76 Regul Toxicol Pharmacol. 2015 Mar; 71(2):235–43. doi: 10.1016/j.yrtph.2014.12.013. Epub 2014 While the study provides useful background data regarding Dec 25. the interpretation of biomonitoring data based on inhibition of erythrocyte cholinesterase, the surrogate key effect in Derivation of human Biomonitoring Guidance Values for chlorpyrifos using a physiologically based humans in Australia is regarded as being plasma pharmacokinetic and pharmacodynamic model of cholinesterase inhibition. cholinesterase inhibition. Arnold SM, Morriss A, Velovitch J, Juberg D, Burns CJ, Bartels M, Aggarwal M, Poet T, Hays S, Price P. A number of biomonitoring surveys have been performed for chlorpyrifos (CPF) and its metabolite (3,5,6-trichloro-2-pyridinol, TCPy); however, there is no available guidance on how to interpret these data in a health risk assessment context. To address this gap, Biomonitoring Guidance Values (BGVs) are developed using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model. The PBPK/PD model is used to predict the impact of age and human variability on the relationship between an early marker of cholinesterase (ChE) inhibition in the peripheral and central nervous systems [10% red blood cell (RBC) ChE inhibition] and levels of systemic biomarkers. Since the PBPK/PD model characterizes variation of sensitivity to CPF in humans, interspecies and intraspecies uncertainty factors are not needed. Derived BGVs represent the concentration of blood CPF and urinary TCPy associated with 95% of the population having less than or equal to 10% RBC ChE inhibition. Blood BGV values for CPF in adults and infants are 6100 ng/L and 4200 ng/L, respectively. Urinary TCPy BGVs for adults and infants are 2100 μg/L and 520 μg/L, respectively. The reported biomonitoring data are more than 150-fold lower than the BGVs suggesting that current US population exposures to CPF are well below levels associated with any adverse health effect.