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  • Title: Regulating and assessing risks of cholinesterase-inhibiting pesticides: divergent approaches and interpretations.
    Author: Carlock LL, Chen WL, Gordon EB, Killeen JC, Manley A, Meyer LS, Mullin LS, Pendino KJ, Percy A, Sargent DE, Seaman LR, Svanborg NK, Stanton RH, Tellone CI, Van Goethem DL.
    Journal: J Toxicol Environ Health B Crit Rev; 1999; 2(2):105-60. PubMed ID: 10230391.
    Abstract:
    This document presents a revised framework for conducting worker and dietary risk assessments for less-than-lifetime exposures to organophosphate or carbamate pesticides based on red blood cell (RBC) or brain acetylcholinesterase (AChE) inhibition or the presence of clinical signs and symptoms. The proposals for appropriate uncertainty factors are based on the biological significance of the cholinesterase (ChE) inhibition noted at the lowest-observed-effect level (LOEL) and the degree of uncertainty in the extrapolation between human and animal data. An extensive evaluation of industry data, not previously summarized, and the available literature indicate that the following risk assessment principles are supportable and protective of human health: Plasma ChE inhibition is not an adverse effect, and therefore should not be utilized in risk assessments. Red blood cell AChE is not associated with the nervous system and inhibition is not per se an adverse (neurotoxic) effect. When available, cholinergic effects or brain AChE inhibition data should take precedence over RBC AChE for determining no-observed-effect levels (NOELs). When available, human RBC AChE inhibition or cholinergic effects data should take precedence over animal data for determining NOELs. Due to the lack of adversity associated with inhibition of RBC AChE, the use of a 10-fold (10x) uncertainty factor from the NOEL is adequate when RBC AChE inhibition data from either animal or human studies are used to assess human risk. Due to greater potential for adversity, NOELs for brain AChE inhibition and cholinergic effects identified in animal studies should receive a default uncertainty factor of 100x; lower uncertainty factors may be used on a case-by-case basis. NOELs based on cholinergic effects noted in human studies should only require a 10x uncertainty factor, since an interspecies extrapolation factor from animals to humans is unnecessary. For RBC and brain AChE activity the threshold for defining a NOEL should be less than or equal to 20% difference from control activity in all species. For risk assessment purposes, duration and route of the study should reflect the expected duration and route of exposure for humans (i.e., a 21-d or 28-d dermal study for subchronic occupational dermal exposure assessment). When dermal data are not available, a subchronic oral toxicity study and an appropriate dermal penetration factor should be used. A general default of 10% absorption should be used, analogous to the United Kingdom and German exposure models that are widely used in Europe. The recommendations in this document are generally consistent with current risk assessment procedures used by Canada, the European Community (EC), and the United Kingdom (UK).
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