Reconsideration of chlorpyrifos Toxicology update JUNE 2019 © Australian Pesticides and Veterinary Medicines Authority 2019 Ownership of intellectual property rights in this publication Unless otherwise noted, copyright (and any other intellectual property rights, if any) in this publication is owned by the Australian Pesticides and Veterinary Medicines Authority (APVMA). Creative Commons licence With the exception of the Coat of Arms and other elements specifically identified, this publication is licensed under a Creative Commons Attribution 4.0 Australia Licence. This is a standard form agreement that allows you to copy, distribute, transmit and adapt this publication provided that you attribute the work. A summary of the licence terms is available from www.creativecommons.org/licenses/by/3.0/au/deed.en. The full licence terms are available from www.creativecommons.org/licenses/by/3.0/au/legalcode. 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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