A review of epidemiologic studies of low-level exposures to organophosphorus insecticides in non-occupational populations

Abstract

This paper systematically reviews epidemiologic studies related to low-level non-occupational exposures to organophosphorus (OP) insecticides. Many of the studies evaluate levels of maternal OP metabolites and subsequent health outcomes in offspring. The studies focused primarily on birth outcomes (e.g., infant body weight or head circumference) and neurodevelopmental (e.g., mental and psychomotor) testing results. The evidence from these studies was reviewed under the Bradford Hill guidelines. Most of the studies assessing exposure based on urinary levels of OP insecticide metabolites used only one or two measurements during pregnancy. The potential for exposure misclassification with this method is largely due to (1) preformed metabolites that are ingested with food, (2) the short elimination half-life of OP insecticides, and (3) lack of specificity to particular OP insecticides for many of the metabolites. For birth outcomes, the majority of reported results are not statistically significant, and the associations are inconsistent within and across studies. There is more within-study consistency for some of the neurodevelopmental testing results, although few associations were examined across several studies. These associations are generally weak, have been replicated only to a limited extent, and require further confirmation before they can be considered established. The OP insecticide levels measured in the epidemiologic studies are too low to cause biologically meaningful acetylcholinesterase inhibition, the most widely used metric for OP insecticide toxicity. Overall, the available evidence does not establish that low-level exposures to OP insecticides cause adverse birth outcomes or neurodevelopmental problems in humans.

Keywords:

• Bradford Hill
• epidemiology
• insecticides
• organophosphorus
• pesticides

Acknowledgements

The authors gratefully acknowledge the review and comments from six anonymous reviewers selected by the editor. The manuscript was significantly strengthened as the result of these reviews. The authors also gratefully acknowledge Mr. Rick Nelson at Exponent for providing a careful editing of the manuscript.

Declaration of interests

The research reported in this paper was sponsored by CropLife America, which represents agrochemical companies that manufacture OP insecticides, under a contract with Exponent. RJR and MG were subcontractors to Exponent. CropLife America reviewed the paper, but the authors had ultimate authority to determine its content. The author's affiliations are listed on the cover page. RR and ETC work for Exponent, which performs risk assessment consulting for companies that produce OP insecticides. RR has served as an expert witness on behalf of defendants for cases involving OP insecticides, though not related to the topics in this paper. RJR has been the Principal Investigator on research grants and research donations to the University of Michigan from Dow Chemical Company and Dow AgroSciences. He has also been appointed by the University of Michigan as the Dow Professor of Toxicology, a professorship endowed by the Dow Foundation. In addition, he has served as a consultant and expert witness on behalf of Dow Chemical Company and Dow AgroSciences.

Notes

¹ To be precise, when formed in the environment, the DAPs are not “metabolites” formed by enzymatic transformations, but rather are degradation products formed by hydrolysis or photolysis. However, we use the term “DAP metabolites” in the paper for brevity.