ISSN No. : 0972-1266

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Newsletter INDIA Vol. 18 No. 3 August 2011

Malathion

Diazinon

CSIR-Indian Institute of Toxicology Research Lucknow, India August 2011 Vol. 18, No. 3

ODDS & ENDS ...... 1 compounds include some of the most toxic chemicals used in agriculture. They are , , Neurobehavioral function and organophosphate use , ciodrin, , , ruelene, among applicators in the Agricultural Health Study...... 1 , supona, TEPP, EPN, HETP, , Organophosphate Pesticide Exposure and Attention in Young , ronnel, , , trichlorfon, , Mexican-American Children: The CHAMACOS Study...... 1 potasan, , , , sevin, and Association of organophosphate pesticide exposure and paraoxo- dimeton. Generally these are , amides, or n a s e w i t h b i r t h o u t c o m e i n m e x i c - a n a m e r i c a n simple derivatives of phosphoric and thiophosphoric acids. Some women...... 1 less toxic compounds of this group are used as systemic Organophosphate esterase inhibitor poisoning from insecticides in animals against parasitc infection. These include a home-made shampoo...... 2 chlorthion, thichlorphon, diazinon, fenchlorphos, and dichlorvos. The organophosphate insecticides can be grouped according to Pollution of soils with organopho-sphorus flame retardants and their toxic action on insects. Many of these compounds are plasticizers...... 2 excreted in milk and are able to cross placental membranes A case report of motor neuron disease in a patient showing causing in offsprings. The chemicals in this class kill significant level of , HCHs and organophosphate metabolites insects by disrupting their nervous system. Unfortunately, these in hair as well as levels of hexane and toluene in blood...... 2 chemicals can also cause toxicity to brain and nervous system of intoxication: Recent neuropathophysiological findings animals and humans. These chemicals inhibit the activity of a key and subsequent impact on medical management prospects...... 2 enzyme in the nervous system called from Organophosphate poisoning in a 12-day-old infant: case working, and this can make people ill. It has been reported that report...... 2 children, with higher levels of organophosphate pesticide metabolites in their urine suffer from Attention- Organophosphate pesticide exposure and residential proximity to nearby fields: evidence for the drift pathway...... 3 Deficit/Hyperactivity Disorder (ADHD) than children with lower levels. Amy Marks, School of Public Health, University of Maternal prenatal and child organophosphate pesticide exposures California (UC) said in a statement "Given that these compounds and children's autonomic function...... 3 are designed to attack the nervous system of organisms, there is Electroencephalogram, cognitive state, psychological disorders, reason to be cautious, especially in situations where exposure clinical symptom, and oxidative stress in horticulture farmers may coincide with critical periods of fetal and child development,". exposed to organophosphate ...... 3 Young children are vulnerable to organophosphate exposure at a Organophosphate and phthalate esters in indoor air: a comparison greater extent than elders, as they have lower levels of between multi-storey buildings with high and low prevalence of sick to detoxify these pesticides. Symptoms of building symptoms...... 4 acute exposure include nausea, headaches, twitching, trembling, A highly sensitive and rapid organophosphate biosensor based on excessive salivation and tearing, difficulty in breathing due to enhancement of CdS-decorated graphene nanocompo site...... 4 paralysis of the diaphragm, convulsions, and some times at higher doses lead to death. are also among Acute and late complications of organophosphate the most common active ingredients in pesticide poisonings as poisoning...... 4 well as suicidal attempts. As per the researchers a number of Organophosphorus poisoning (acute)...... 4 less-toxic alternatives to organophosphate pesticides are Organophosphate poisoning in pregnancy...... 5 available these are: Pheromones: chemicals secreted by insects Comparative protective effects of HI-6 and MMB-4 against for communication--to disrupt insect mating; Cultural controls: organophosphorous nerve agent poisoning...... 5 crop rotations, manipulating planting dates, reducing of pest habitats and improving crop vigor; Less toxic, more pest-specific Gene-environmental interactions and organophosphate alternative insecticides toxicity...... 5 Enzymes and bioscavengers for prophylaxis and treatment of organophosphate poisoning...... 6 Editors DID YOU KNOW ? ...... 6 Dr. Poonam Kakkar CURRENT CONCERNS...... 7 Dr. Anvita Shaw REGULATORY TRENDS ...... 7 ON THE LIGHTER SIDE...... 8 Published by : Distributed Information Centre on Toxic Chemicals CONFERENCES ...... 8 Environmental Information System (ENVIS) BOOK STOP ...... 9 at CSIR-Indian Institute of Toxicology Research MINI PROFILE OF MALATHION ...... 9 Lucknow, India

ENVIS NEWSLETTER August 2011 Vol. 18, No. 3

Neurobehavioral function and motor speed and visual scanning; [Environ Health Perspect 118:1768- organophosphate insecticide use and parathion was associated with 1774.] better performance on a test of among pesticide applicators in the Association of organophosphate sustained attention. Several assoc- Agricultural Health Study. pesticide exposure and paraoxo- iations varied by state. Overall, Although persistent decrements in nase with birth outcome in mexic- authors found no consistent evidence cognitive function have been anamerican women. of an association between OP observed among persons who have pesticide use and adverse NB test Epidemiologic studies suggest that recovered from clinically overt performance among this older maternal organophosphorus (OP) organophosphate (OP) pesticide sample of pesticide applicators. pesticide exposure is associated with poisoning, little is known about the Potential reasons for these mostly poorer fetal growth, but findings are cognitive effects of chronic OP null results include a true absence of inconsistent. The authors explored exposures that do not result in acute effect as well as possible selective whether paraoxonase (PON1), a key poisoning. To examine associations participation by healthier applicators. enzyme involved in detoxification of between long-term pesticide use and OPs, could be an effect modifier in neurobehavioral (NB) function, NB [Neurotoxicol Teratol. 2011 Aug 28. this association. The study population tests were administered to licensed (doi:10.1016/j.ntt.2011.08.014 Epub included 470 pregnant women pesticide applicators enrolled in the ahead of print)] enrolled in the CHAMACOS Study, a Agricultural Health Study (AHS) in Organophosphate Pesticide longitudinal cohort study of mothers Iowa and North Carolina. Between Exposure and Attention in Young and children living in an agricultural 2006 and 2008, 701 male participants Mexican-American Children: The region of California. The authors completed nine NB tests to assess CHAMACOS Study analyzed urine samples collected memory, motor speed and coordin- from mothers twice during pregnancy ation, sustained attention, verbal Organophosphate (OP) pesticides for dialkyl phosphate (DAP) learning and visual scanning and are well-known neurotoxicants that metabolites of OP pesticides. They processing. Data on ever-use and have been associated with neuro- analyzed maternal and fetal (cord) lifetime days of use of 16 OP behavioral deficits in children. blood samples for PON1 genotype pesticides were obtained from AHS Authors evaluated attention-related (PON1(192) and PON1(-108)) and interviews conducted before testing outcomes among Mexican-American enzyme activity (paraoxonase and between 1993 and 2007 and during children participanting in the arylesterase). Infant birth weight, the NB visit. The mean age of CHAMACOS study (331 children 3.5 participants was 61years (SD=12). years and 323 children 5 years of head circumference, and gestational Associations between pesticide use age), and measured urinary dialkyl age were obtained from medical and NB test performance were phosphate (DAP) metabolites in the records. Infants' PON1 genotype and estimated with linear regression children and in their mothers during activity were associated with birth controlling for age and outcome- pregnancy to determine OP outcome, but mothers' were not. specific covariates. NB test exposure. The authors report that Infants with the susceptible PON1(- performance was associated with prenatal DAP levels were positively 108TT) genotype had shorter lifetime days of use of some but not significantly associated with gestational age (β=-0.5 weeks, 95% pesticides. Ethoprop was significantly maternal reports of attention Confidence Interval (CI): -0.9, 0.0) associated with reduced perfor- problems or attention deficit/ and smaller head circumference (β=- mance on a test of motor speed and hyperactivity disorder (ADHD) at 3.5 0.4 cm, 95% CI: -0.7, 0.0) than those visual scanning. Malathion was years, and were significantly with the PON1(-108CC) genotype. significantly associated with poor associated with these outcomes at 5 Infants' arylesterase and paraox- performance on a test of visual years. Some associations appeared onase activity were positively scanning and processing. Conver- to be modified by sex, with associated with gestational age. sely, authors observed significantly associations found only among boys. There was some evidence of effect better test performance for five OP There was also limited evidence of modification with DAPs: maternal pesticides. Specifically, chlorpyrifos, associations between the outcomes DAP concentrations were associated coumaphos, parathion, phorate, and and DAP levels measured in the with shorter gestational age only were associated children. The authors conclude that in among infants of the susceptible with better verbal learning and utero DAPs and, to a lesser extent, PON1(-108TT) genotype (p- memory; coumaphos was associated DAPs in children, were associated value(interaction)=0.09). However, with better performance on a test of adversely with attention. maternal DAP concentrations were

ENVIS NEWSLETTER 1 August 2011 Vol. 18, No. 3 associated with larger birth weight (p- atmospheric sources has to be [Toxicol Appl Pharmacol. 2011 Aug 6. value(interaction)=0.06) and head considered in risk assessments. (doi:10.1016/j.taap.2011.07.022 circumference (p-value (interaction) [J Environ Monit. 2011 Aug 24.( Epub ahead of print) ] <0.01) in infants with non-susceptible doi:10.1039/c1em10538h Epub Nerve agent intoxication: Recent genotypes.The conclusion was that ahead of print)] neuropathophysiological findings infants whose PON1 genotype and A case report of motor neuron and subsequent impact on enzyme activity levels suggested that medical management prospects. they might be more susceptible to the disease in a patient showing effects of OP pesticide exposure had significant level of DDTs, HCHs This manuscript provides a survey of decreased fetal growth and length of and organophosphate metabolites research findings catered to the gestation. PON1 may be another in hair as well as levels of hexane development of effective counter- factor contributing to preterm or low and toluene in blood. measures against nerve agent birth weight birth. Motor neuron disease is a poisoning over the past decade. New neuropathophysiological distinctive [PLoS One. 2011;6(8):e23923. ] devastating neurodegenerative condition, with the majority of features as regards organoph- Organophosphate acetylcholine sporadic, non-familial cases being of osphate (OP) intoxication are esterase inhibitor poisoning from unknown etiology. Several epidemiol- presented. Such leading neurop- a home-made shampoo. ogical studies have suggested that athophysiological features include Organophosphate acetylcholine occupational exposure to chemicals recent data on nerve agent-induced esterase inhibitor poisoning is a may be associated with disease neuropathology, related peripheral or major health problem in children. pathogenesis. Authors report the central nervous system inflammation Here authors report an unusual case of a patient developing and subsequent angiogenesis cause of organophosphate acetyl- progressive motor neuron disease, process. Hence, leading counter- esterase inhibitor poisoning. who was chronically exposed to measures against OP exposure are Two children were admitted to the pesticides and organic solvents. The down-listed in terms of pre-treatment, pediatric intensive care unit due to patient presented with leg spasticity protection or decontamination and organophosphate acetylcholine and developed gradually clinical emergency treatments. The final esterase inhibitor poisoning after signs suggestive of amyotrophic chapter focuses on the description of exposure from a home-made lateral sclerosis, which was the self-repair attempt encountered in shampoo that was used for the supported by the neurophysiologic lesioned rodent brains, up to 3months treatment of head lice. Owing to no and radiological findings. This report after poisoning. Indeed, an obvious source of poisoning, the is an evidence based case of increased proliferation of neuronal diagnosis of organophosphate combined exposure to organoc- progenitors was recently observed in acetylcholine esterase inhibitor hlorine (DDTs), organophosphate injured brains of mice subjected to poisoning in one of these patients pesticides (OPs) and organic soman exposure. Subsequently, the solvents as confirmed by laboratory was delayed. Both patients had an latter experienced a neuronal analysis in samples of blood and hair uneventful recovery. Organophos- regeneration in damaged brain confirming systematic exposure. The phate acetylcholine esterase inhibitor regions such as the hippocampus concentration of non-specific p o i s o n i n g f r o m h o m e - m a d e and amygdala. The positive effect of a dialkylphosphates metabolites shampoo is possible. In cases where cytokine treatment on the neuronal (DAPs) of OPs in hair (dimethypho- the mode of poisoning is unclear, regeneration and subsequent pshate (DMP) 1289.4pg/mg and direct questioning about the use of cognitive behavioral recovery are diethylphosphate (DEP) 709.4pg/ home-made shampoo is warranted, also discussed in this review. For the m g ) a n d o f D D Ts ( o p D D E in these cases the skin and first time, brain cell therapy and 484.0pg/mg, ppDDE 526.6pg/mg, neuronal regeneration are consi- particularly the scalp should be rinsed opDDD 448.4pg/mg, ppDDD+opDDT thoroughly as soon as possible. dered as a valuable contribution 259.9pg/mg and ppDDT 573.7pg/mg) towards delayed treatment against [J Emerg Trauma Shock. 2011 were considerably significant. OP intoxication. To date, efficient Jul;4(3):433-4.] Toluene and n-hexane were also delayed treatment was lacking in the Pollution of soils with organopho- detected in blood on admission at therapeutic resources administered hospital and quantified (1.23 and sphorus flame retardants and to patients contaminated by nerve 0.87µg/l, respectively), while plasticizers. agents. 3months after hospitalization blood The detection of the three organ- testing was found negative for [Toxicol Appl Pharmacol. 2011 Sep ophosphate esters TCEP, TCPP and toluene and n-hexane and hair 15;255(3):229-41. ] TBEP in soil samples indicates that analysis was provided decrease Organophosphate poisoning in a pollution of soils from diffuse levels of HCHs, DDTs and DAPs. 12-day-old infant: case report.

ENVIS NEWSLETTER 2 August 2011 Vol. 18, No. 3

A 12-day-old infant girl was admitted because of their effects on 95% CI: -6.29 to -0.09, p=0.04) only at with increasing lethargy and fibers, may interfere with the 5 years. In addition, there were no respiratory distress. Initial treatment functions of the autonomic nervous significant differences in ANS was for pneumonia but deterioration system (ANS). Authors conducted a measures for 5-year-olds with despite appropriate treatment study to assess the relation of in utero consistently high versus low DAPs. prompted review of her diagnosis and and child OP pesticide exposures and Although authors observe some consideration of organophosphate children's autonomic nervous system evidence of ANS dysregulation in poisoning. There was a brisk (ANS) dysregulation under resting infancy, authors report no consistent response to . This is the and challenge conditions. They associations of maternal and child OP youngest infant reported to have hypothesized that children with high pesticide exposure, as measured by been exposed to poisoning by OP levels would show parasy- urinary DAPs, on children's ANS (HR, organophosphates. mpathetic activation and no RSA, and PEP) regulation during [Ann Trop Paediatr. 2011;31(3):263- sympathetic activation during rest resting and challenging conditions up 7.] and concomitant parasympathetic to age 5 years. and sympathetic activation during Organophosphate pesticide [Neurotoxicology. 2011 Jun 29. [Epub challenging conditions. OP expos- ahead of print]] e x p o s u r e a n d r e s i d e n t i a l ures were assessed by measuring proximity to nearby fields: urinary dialkylphosphate metabolites Electroencephalogram, cognitive evidence for the drift pathway. (DAPs, total diethyls-DEs, and total state, psychological disorders, Residential proximity to pesticide- dimethyls-DMs) in maternal and clinical symptom, and oxidative treated farmland is an important children's spot urine samples. ANS stress in horticulture farmers pesticide exposure pathway. In- regulation was examined in relation exposed to organophosphate person interviews and biological to maternal and child DAPs in 149 pesticides. samples were collected from 100 children at 6 months and 1 year, 97 at The aim of this paper was to study the farmworker and 100 non-farmworker 3 1/2 years and 274 at 5 years. toxicity of organophosphate (OP) adults and children living in Eastern Authors assessed resting and pesticides in exposed farmers for Washington State. Authors examined reactivity (i.e., challenge minus rest) electroencephalography, cognitive the relationship of residential measures using heart rate (HR), state, psychological disorders, proximity to farmland to urinary respiratory sinus arrhythmia (RSA), clinical symptom, oxidative stress, metabolite concentrations of dime- and preejection period (PEP) during acetylcholinesterase, and DNA thylphosphate (DMTP) and levels of the administration of a standardized damage. A comparative cross- pesticide residues in house dust. protocol. Cross-sectional (at each sectional analysis was carried out in DMTP concentrations were higher in age) and longitudinal regression 40 horticulture farmers who were farmworkers than non-farmworkers models were conducted to assess OP exposed to OPs in comparison to a (71 µg/L 6 µg/L) and in farmworker and ANS associations. To estimate control group containing 40 healthy children than non-farmworker cumulative exposure at 5 years, subjects with the same age and sex children (17 µg/L vs 8 µg/L). authors used an area-under-the- and education level. Lipid perox- Compared to non-farmworker concentration-time-curve (AUC) idation (LPO), superoxide dismutase households, farmworker households methodology. They also evaluated (SOD), catalase, glutathione had higher levels of azinphos-methyl whether children with consistently peroxidase, DNA damage, total (643 ng/g vs 121 ng/g) and high versus low DAP concentrations antioxidant capacity (TAC), total (153 ng/g vs 50 ng/g). Overall, a 20% had significantly different mean ANS molecules, and acetylcholinesterase reduction in DMTP concentration was scores at 5 years. Child DMs and (AChE) activity were measured in the observed per mile increase in DAPs were significantly negatively blood of subjects. Clinical exami- distance from farmland. Lower OP associated with resting RSA at 6 nation and complete blood test were metabolite concentrations correlated months and maternal DMs and child undertaken in order to record any with increasing distance from DEs were significantly positively abnormal sign or symptoms. farmland. associated with resting PEP at 1 year. Cognitive function, psychological No associations with resting were [J Occup Environ Med. 2011 symptoms, and psychological observed in 3 1/2- or 5-year-old Aug;53(8):884-91.] distress were examined and recor- children nor with reactivity at any age. ded. Comparing with controls, the Maternal prenatal and child There was no significant relationship farmers showed higher blood levels organophosphate pesticide between the reactivity profiles and of SOD and LPO while their TAC e x p o s u r e s a n d c h i l d r e n ' s maternal or child DAPs. Cumulative decreased. Farmers showed clinical autonomic function. maternal total DEs were associated symptoms such as eczema, breath- Organophosphate pesticides (OP), with low HR (-3.19bpm decrease; ing muscle weakness, nausea, and

ENVIS NEWSLETTER 3 August 2011 Vol. 18, No. 3 saliva secretion. Regarding cognitive within and between buildings. baryl] from 2 µg mL?¹ up to 2 µg mL?¹ function, the orientation, registration, Association with building chara- with a detection limit of 0.7 µg mL?¹, attention and calculation, recall, and cteristics has been examined as well which provides a new promising tool language were not significantly as association with specific sources for analysis of enzyme inhibitors. different in farmers and controls. by combining chemical analysis and [Anal Chim Acta. 2011 Jun 10;695(1- Among examinations for psych- exploratory uni- and multivariate data 2):84-8.] ological distress, only labeled analysis. The study contributes to the somatization was significantly higher overall perspective of levels of Acute and late complications of in farmers. The present findings organophosphate and phthalate organophosphate poisoning. indicate that oxidative stress and in indoor air enabling comp- To describe the acute and late inhibition of AChE can be seen in arison with other studies. The results complications of organophosphate chronically OP-exposed people but indicated little or no difference in the (OP) poisoning a total of 300 patients incidence of neuropsychological concentrations of the target subs- with organophosphate poisoning tances between the two risk admitted to the Medical ICU were classifications of the buildings. The included. Baseline investigations differences between the apartments included blood complete picture, sampled within (intra) buildings were urea, creatinine, arterial blood gas greater than the differences between values, and serum cholinesterase (inter) buildings. The concentrations levels. Data was retrieved from the measured in air ranged up to 1200 ng files on a structured proforma. m(-3) for organophosphate esters Studied variables included gender, and up to 11000 ng m(-3) for mode of exposure, acute (occuring phthalate esters. Results in terms of within 4 weeks) and delayed sources were discerned e.g. PVC (occuring after 4 weeks onwards) flooring is a major source of complications There were 50 disorders seems a complex multi- benzylbutyl phthalate in indoor air. (16.66%) males and 250 (83.33%) variate phenomenon that might be [J Environ Monit. 2011 Jul;13(7): females with ratio of 1:5. Two hundred seen in long-term high-dose 2001-9.] and forty eight (82.6%) had ingested exposure situations. Use of supple- while 18 (6%) had inhaled the poison. mentary antioxidants would be useful A highly sensitive and rapid Acute complications included fits in in the treatment of farmers. organophosphate biosensor 50 (16.66%) bradycardia in 30 (10%) based on enhancement of CdS- [Toxicol Ind Health. 2011 Jun 1. [doi: and hyperglycemia in 15 (5%) decorated graphene nanocompo 10.1177/0748233711407243 (Epub patients. Delayed complications site. ahead of print)] (after 4 weeks and later) included This work reports a rapid and monoplegia and mild sensory loss of Organophosphate and phthalate sensitive organophosphates (OPs) lower limbs in 4 (2.66%) and esters in indoor air: a comparison amperometric biosensor based on paraplegia and weakness of upper between multi-storey buildings acetylcholinesterase (AChE) immo- limbs in 2 (0.66%) patients each. A with high and low prevalence of bilized on CdS-decorated graphene total of 50 patients died due to sick building symptoms. (CdS-G) nanocomposite. The as- different complications in acute An extensive study has been prepared biosensor shows high period making a mortality rate of conducted on the prevalence of affinity to acetylthiocholine (ATCl) 16.66%. Frequency of acute organophosphorous flame retardants with a Michaelis-Menten constant organophosphate (OP) poisoning /plasticizers and phthalate ester (K(m)) value of 0.24 mM. A rapid complications is much higher and plasticizers in indoor air. The targeted inhibition time (2 min) is obtained due related with high mortality and substances were measured in 45 to the integration of the CdS-G morbidity and where as late multi-storey apartment buildings in nanocomposite. Based on the complications are less frequent and Stockholm, Sweden. The apartment inhibition of OPs on the enzymatic less life threatening. buildings were classified as high or activity of the immobilized AChE, and [J Coll Physicians Surg Pak. 2011 low risk with regard to the reporting of used as the model May;21(5):288-90.] sick building symptoms (SBS) within compound, the resulting biosensor Organophosphorus poisoning the project Healthy Sustainable exhibits excellent performance for (acute). Houses in Stockholm (3H). Air OPs detection including good samples were taken from two to four reproducibility, acceptable stability, Acetylcholinesterase inhibition by apartments per building (in total 169 and a reliable linear relationship organophosphorus pesticides or apartments) to facilitate comparison between the inhibition and log[car- organophosphate nerve agents can

ENVIS NEWSLETTER 4 August 2011 Vol. 18, No. 3 cause acute parasympathetic system atropine injection until the trach- development in a number of other dysfunction, muscle weakness, eobronchial tree is cleared of the countries. The oxime MMB-4 has not seizures, coma, and respiratory secretions and most secretions were yet been studied clinically, but is failure. Prognosis depends on the dried. In addition, ventilatory care fielded by the Czech Republic, and is dose and relative toxicity of the was needed in five women. Two being developed by the United States specific compound, as well as patients (9.52%) died of the armed services as a replacement for pharmacokinetic factors. Authors organophosphorus poisoning during the currently fielded 2-PAM. This conducted a systematic review and the acute stage of poisoning and review compares the effectiveness of aimed to answer the following clinical three patients were lost to follow-up. HI-6 and MMB-4 against nerve agent question: What are the effects of One woman had a spontaneous threats where comparisons can be treatments for acute organoph- abortion. The remaining 15 women made. HI-6 has been demonstrated osphorus poisoning? They searched: had no significant complication to be generally a superior reactivator Medline, Embase, The Cochrane during pregnancy or labour and of nerve agent inhibited enzyme, Library, and other important delivery. There was no congenital particularly with human and non- databases up to April 2010. Authors abnormality and no neurological human primate derived enzyme, and included harms alerts from relevant deficit in any baby. However, long- has also shown better protective organisations such as the US Food term follow-up of neonates was effects against the lethality of most and Drug Administration (FDA) and lacking in the study population. OP agents in a variety of species. the UK Medicines and Healthcare [J Obstet Gynaecol. 2011 May; Both compounds appear to be clearly products Regulatory Agency 31(4):290-2.] superior to the available oximes, ( M H R A ) . A u t h o r s f o u n d 6 2 and 2-PAM. systematic reviews, RCTs, or Comparative protective effects of H I - 6 a n d M M B - 4 a g a i n s t [Toxicology. 2011 Jul 29;285(3):90-6. observational studies that met our ] inclusion criteria. They performed a organophosphorous nerve agent GRADE evaluation of the quality of poisoning. Gene-environmental interactions evidence for interventions. In this The oximes (2-PAM), its and organophosphate toxicity. systematic review authors present dimethanesulphonate salt derivative Organophosphates (OPs) are an information relating to the effectiv- P2S, and obidoxime (toxogonin) are important class of insecticides that in eness and safety of the following currently licensed and fielded for the the UK have been widely used for interventions: activated charcoal treatment of chemical warfare (CW) treating sheep for ectoparasites as (single or multiple doses), alpha(2) organophosphorous (OP) nerve well as in other sectors of the farming adrenergic receptor agonists, agent poisoning. While they are industry. Health problems associated atropine, benzodiazepines, butyryl- effective against several of the with acute OP toxicity are well defined cholinesterase replacement therapy, identified threat CW OP agents, they but, ill-health induced by chronic cathartics, extracorporeal clearance, have little efficacy against others e x p o s u r e s t o O P s r e m a i n s gastric lavage, glycopyrronium such as soman (GD) and controversial. A substantial number of bromide (glycopyrrolate), ipec- (CF). In addition, they are also sheep farmers complain of chronic ill- acuanha (ipecac), magnesium significantly less effective than other health which they attribute to sulphate, milk or other home remedy investigational oximes against the repeated exposure to OPs. If OPs immediately after ingestion, N- nerve agent known as Russian VX were associated with chronic ill- methyl-D-aspartate receptor anta- (RVX). Among the oximes currently health then individuals with specific gonists, organophosphorus hydrola- being investigated, two in particular, defects in OP might be ses, oximes, removing contaminated HI-6 (asoxime) and MMB-4 (ICD-039, expected to be at greater risk of ill- clothes and washing the poisoned methoxime) have been proposed as health following exposure. To person, and sodium bicarbonate. replacement therapies for the examine such a hypothesis, the [Clin Evid (Online). 2011 May currently licensed oximes. HI-6 has characterisation of both OP exposure 17;2011. pii: 2102.] been safely used in individuals to and those pathways which lead to the treat OP insecticide poisoning, as formation and removal of the active Organophosphate poisoning in well as in human volunteers, although OP metabolites becomes important. pregnancy. its efficacy against OP nerve agent A wide range of OPs have previously Organophosphate poisoning during poisoning in humans cannot be been used to treat sheep but currently pregnancy is rarely reported in the demonstrated due to ethical consi- the only OP licenced for treating literature. In this study, authors report derations. It is currently available for sheep is diazinon. Immediately after the outcome of 21 cases of use in defined military settings in treatment, farmers' urines contain organophosphate poisoning during Canada, Sweden and the Czech detectable levels of OP metabolites pregnancy. All patients received Republic, and is also under but few farmers have a significant

ENVIS NEWSLETTER 5 August 2011 Vol. 18, No. 3 decrease in plasma cholinesterase an increased risk of self-reported poisoning causes significant activity. Diazinon, like chlorpyrifos, is chronic ill-health, a result consistent morbidity and mortality, particularly in an organothiophosphate which is with the hypothesis that this ill-health the developing world, with upwards of metabolised, particularly by cytoc- may have been caused by OPs. 3 million people poisoned each year. hrome p450s, to the corresponding Studies in other populations exposed Although OP poisoning is not active form. CYP metabolism to pesticides also show associations common in developed countries, also leads to the inactivation of the between ill-health and PON1 Q192R recently greater attention has been parent compound and the relative polymorphisms but not consistently given to these chemicals because of balance of inactivation and activation so. This is not surprisingly given that their similarity to chemical warfare can depend upon the specific OP and exposure is often poorly chara- agents. Despite the agricultural use the CYP isoform. OP oxons are cterised. In vivo models also suggest of OP pesticides for roughly 60 years, inactivated by serum paraoxonase that PON1 genotypes may have little no new therapies have been (PON1) and mice lacking PON1 influence on susceptibility at low developed since the 1960s. A activity are susceptible to oxon and doses of the parent OP. Hence further promising field of novel antidotes for parent OP induced toxicity. PON1 work is required not only to better OP poisoning, OP hydrolases, has polymorphisms at positions 192 (R characterise OP exposure in humans recently garnered increased support. form with arginine at 192 and Q with populations but also to identify those These bacterial enzymes have glutamine) and 55 (L form with a populations susceptible to OP demonstrated tremendous proph- leucine and a M form with toxicity. ylactic and antidotal efficacy against a methionine) influence paroxonase few different OP classes in animal [Toxicology. 2010 Dec 30;278(3):294- models. These studies, as well as the activity. The effect of the Q192R 304. ] polymorphism is substrate specific limitations and challenges of therap- with reports indicating that diazoxon Enzymes and bioscavengers for eutic development of these enzymes, are discussed. is metabolised less by the R isoform. prophylaxis and treatment of In a study of sheep farmers within the organophosphate poisoning. [Front Biosci (Schol Ed). 2010 Jan UK, the R allele was associated with Organophosphorus (OP) pesticide 1;2:209-20.]

qThe wide use of organoph on several crops to control a organophosphate insecticides. osphates is based on several variety of insect/ pests). ¨In general, insects have not factors: ¨Because of this broad spectrum of d e v e l o p e d r e s i s t a n c e t o ¨They are relatively inexpensive. activity, one organophosphate organophosphates as they have ¨They are broad spectrum (most might control the insects that to some other pesticides. organo phosphates can be used would require three or four non-

Crop-wise consumption of insecticides in India

Plantation Others Crops 8% Cotton Fruits & 8% 54% Vegetables 13%

Rice 17%

(Source: http://mv.picse.net/pesticides/cotton/toxicity-of-insecticides/)

ENVIS NEWSLETTER 6 August 2011 Vol. 18, No. 3

qOrganophosphate toxicity is due neuromuscular transmission qOrganophosphate compounds to the ability of these compounds impairment. vary greatly in their toxic to inhibit acetylcholinesterase at qMany of these compounds are capabilities and have the cholinergic junctions of the excreted in milk and are able to advantage over other types of nervous system resulting in cross placental membranes insecticides in that they produce respiratory, myocardial and causing toxicity in offspring. little or no tissue residues

Mechanism of Organophosphate Toxicity (Source: http://depts.washington.edu/opchild/acute.html) CURRENT CONCERNS

Organophosphate pesticides have have greater acute toxicity, posing of foetuses and young children. rapid degradability as compared to considerable risks to people exposed Organophosphates are one of the persistent pesticides. to this pesticide. Organophosphate most common causes of poisoning They hydrolyse easily on exposure to pesticides are of great concern for worldwide, and used frequently for sunlight, air, and soil. Their ability to scientists as well as regulators suicides in agricultural areas. degrade make them a better and because they work by irreversibly Organophosphorus pesticides can attractive alternative to the persistent blocking an enzyme that's critical to be absorbed by all routes, including organochlorine pesticides, such as nerve function in both bugs and inhalation, ingestion, and dermal DDT, and . Although people. Even at relatively low levels, absorption organophosphates degrade more organophosphates may be most easily than the , they hazardous to the brain development

REGULATORY TRENDS

In 1958 Government of India studied in 1964-67 by an Expert insecticides with a view to prevent appointed a Commission of enquiry Committee of Indian Council of risks to human beings and animals. to suggest Inter-alia remedial Agricultural Research headed by The enforcement of Act was measures following a number of Prof. M.S. Thacker. Based on the transferred to the Ministry of deaths in Kerela and Tamil Nadu by recommendations of the Expert Agriculture in the year 1970 by the poisoning through the consumption Committee a comprehensive Ministry of Health and family of imported wheat contaminated with Insecticides Act was passed in 1968 Planning. Department of Agriculture pesticide. The whole question of to regulate the import, manufacture, framed the rules and constituted pesticide use and legislation was sale, transport, distribution and use of Central insecticides Board and

ENVIS NEWSLETTER 7 August 2011 Vol. 18, No. 3

Registration committee. The states licence for their manufacture, nuisance caused by public health were simultaneously advised to formulation and sale are dealt with at pests and the health hazards appoint all functionaries mentioned in the State level. With the enforcement involved in their use have been the Act. After the stage was fully set, of the Insecticides Act in the country, minimised to a great extent. For the all the provisions of the Insecticides pesticides of very high quality are effective enforcement of the Act were brought into force with effect made available to the farmers and Insecticides Act, the following bodies from 1st August, 1971. In the Act and general public for house-hold use. have been constituted at the Central the Rules framed there under, there is They help in protecting the level - compulsory registration of the agricultural crops from the ravages of ?Central Insecticides Board pesticides at the Central level and pests, humans from diseases and ?Registration Committee

Organizational Chart of Central Insecticides Board And Registration Committee

Chairman Chairman Central Insecticides Board Registration Committee

Secretary, Central Insecticides Board And Registration Committee

Bio-Efficacy Chemistry Medical Packaging & Legal Unit Administration Unit Toxicology Labelling Unit Unit Unit (Source: http://cibrc.nic.in/about_us.htm)

ON THE LIGHTER SIDE qDr. Francis Gunther, known to his looked for little bits of a few things He goes down another thirty feet, peers as the father of pesticide in some things; today we look for and the guy with no equipment residue chemistry, once said less of more things in anything; stays with him. He takes out a regarding humankind's ever tomorrow we will look for nothing waterproof chalkboard and writes, increasing ability to detect in everything." "How the hell can you stay down infinitesimal quantities of qA deep-sea diver is twenty feet this deep without equipment?" pesticides in food and the below sea level when he sees The guy takes the chalkboard and paranoia that attends it in the another guy with no scuba gear. writes, "You idiot, I'm drowning." minds of some: "Yesterday we

CONFERENCES q14th International Fresenius q2nd International Conference on on Pesticide and Environm AGRO Conference: Behaviour “Agrochemicals Protecting ental Safety & 8th International of Pesticides in Air, Soil and Crops, Health and Natural Workshop on Crop Protection Water E n v i r o n m e n t - R o l e o f Chemistry and Regulatory 25- 26 June 2012 in Mainz/ Chemistry for Sustainable Harmonization Germany Agriculture” 15-18 February q15-20 September 2012 in Beijing h t t p : / / w w w . a k a d e m i e - 2012 in New Delhi (India) - China fresenius.de/english/konferenz/o http://www.apchne.com http://www.2012iupac.com utput.php?kurs=295 q4th International Symposium

ENVIS NEWSLETTER 8 August 2011 Vol. 18, No. 3 BOOK STOP

Toxicology of Organophosphate & Published : DEC-2005 Compounds ISBN : 0-12-088523-9/978-0- 12-088523-7 Publisher : ACADEMIC PRESS

The Complete Technology Book on Pesticides, Insecticides, Fungicides and Herbicides with Formulae & Processes Published : 2003 Publisher : National Institute of Author : H. Panda Industrial Research Edited : Ramesh Gupta ISBN : 8186623728 MINI PROFILE

CHEMICALNAME MALATHION hilthion-; karbofos-; kill-a-mite-; kop- MOLECULAR WEIGHT SYNONYM American-cyanamid- thion-; kypfos-;malacide-; malafor-; 330.36000000000001 4,049-; s-(1,2-bis(carbethoxy)ethyl) malagran-; malakill-; malamar-50-; PROPERTY Colour- Clear amber o,o-dimethyl dithiophosphate; s-(1,2- malasol-; malaspray-; malataf-; liquid; Odour -mercaptan-like odour; bis(ethoxycarbonyl)ethyl) o,o- malathiazol-; ortho-malathion-; Solubility- soluble in water: 45 ppm at dimethyl phosphorodithioate; s-1,2- malathion-e50-; malathion-lv- 25 °C; miscible in most organic bis(ethoxycarbonyl)ethyl-o,o- concentrate-; malathon-; malathyl-; solvents; BP- 156-157 °C; MP- 2.85 dimethyl ; butanedioic malatol-; malatox-; malmed-; °C; Density- 1.23 at 25 o C; acid,((dimethoxyphosphinothioyl)thi malphos-; mercaptosuccinic-acid- Compatibilty- incompatible with o)-, diethyl ester; camathion-; diethyl-ester-; mercaptothion-; alkaline pesticides and is corrosive to carbetovur-; carbetox-; carbofos-; m o s c a r d a - ; n c i - c 0 0 2 1 5 - ; . carbophos-; caswell-no-535-; oleophosphothion-; paladin-; USES Malathion is an effective chemathion-; cimexan-; cythion-; phosphothion-; prioderm-; sadofos-; insecticide against most household diethyl-mercaptosuccinate,-o,o- sadophos-; sf-60-; siptox-i-; sumitox-; pests and has been used to control dimethyl-thiophosphate-; o,o- tak-; tm-4049-; vetiol-; xmc-; zithiol- houseflies, cockroaches, mosquitos, dimethyl s-(1,2-dicarbethoxyethyl) RTECS NO WM8400000 , animal ectoparasites and dithiophosphate; o,o-dimethyl s-(1,2- CAS NO 121-75-5 human head and body lice. dicarbethoxyethyl)phosphorodithioat MOLECULAR FORMULA TOXICITY DATA e ; o , o - d i m e t h y l s - 1 , 2 C10H19O6PS2 Oral- Rat : LD : 290 mg/kg di(ethoxycarbamyl)ethyl phosphoro 50 Oral- Mus : LD :190 mg/kg dithioate;o,o-dimethyldithiopho 50 sphatediethylme rcaptosuccinate-; Dermal- Rabbit : LD50: 4100 mg/kg o,o-dimethyl-dithiophosphate-of- Oral-Guinea-pig: LD50: 570 mg/kg d i e t h y l - m e r c a p t o s u c c i n a t e - ; ANTIDOTE Atropine dorthion-; ethiolacar-; etiol-; extermathion-; flair-; fog-3-; forthion-; fosfothion-; fosfotion-; fyfanon-;

Route of Symptoms First aid Target organs Exposure

Inhalation/ Headache, nausea, , Fresh air, rest, half-upright- position, rinse Central Nervous Ingestion dizziness, muscle weakness, mouth. Give slurry of activated charcoal in System sluggishness, difficulty in water to drink. Refer for medical attention. breathing and nervousness.

Contact Eye tearing, & sweating Rinse eyes with water and skin with Skin and Eyes water and soap. Refer for medical attention. STORAGE and DISPOSAL Should be stored in clearly labelled rigid and leak proof containers. No food or drink should be stored in the same compartment. Decontaminated containers should not be used for food and drink. Containers that are not decontaminated should be burned or should be crushed and buried below topsoil. Care must be taken to avoid subsequent contamination of water sources.

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