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Dimethoate is an organophosphate (OP) pesticide used to control a wide variety of insects on agricultural crops and ornamentals. To ensure that dimethoate is used safely, it is important to determine exposure levels that protect against adverse effects at all life stages, including the developing fetus, infant, and child. Based on an analysis of a developmental neurotoxicity (DNT) study, a cholinesterase (ChE) sensitivity study, a cross-fostering study, and several single- and multigenerational reproductive toxicity studies, two potential critical endpoints for dimethoate were identified: brain ChE inhibition (ChEI) in adult females, and pup mortality. An initial evaluation concluded that pup mortality was a preferable endpoint, based on an increased number of pup deaths born to dams dosed with ≥3 mg/kg dimethoate via oral gavage. Closer examination, however, revealed that the pup deaths were clustered in a small number of litters in which the dams providing postnatal care exhibited maternal care deficits. When the data were analyzed using the dam as the unit of statistical significance, a significant increase in the average litter proportion of pup deaths was observed only when the dams were dosed postnatally with 6 mg/kg dimethoate while they were raising the pups. Gestational exposure (i.e., during pregnancy only) to 6 mg/kg dimethoate exerted no effect on pup survival. This leads to the conclusion that it is postnatal exposure of the nursing dams that is associated with pup mortality. Furthermore, a previous benchmark dose (BMD) meta-analysis approach revealed that BMDL10 for adult females (the lower 95% bound of the dose resulting in a 10% reduction in the parameter of interest) for ChEI was > 3-fold lower than the BMDL10 for pup mortality (0.19 and 0.68 mg/kg, respectively). Overall, this study underscores the importance of using the dam as the unit of statistical significance when assessing data collected in the perinatal period, and it is concluded that adult brain ChEI is the correct critical endpoint for assessing risk of dimethoate toxicity. [ABSTRACT FROM AUTHOR]

A complete mode of action human relevance analysis—as distinct from mode of action (MOA) analysis alone—depends on robust information on the animal MOA, as well as systematic comparison of the animal data with corresponding information from humans. In November 2003, the International Life Sciences Institute's Risk Science Institute (ILSI RSI) published a 2-year study using animal and human MOA information to generate a four-part Human Relevance Framework (HRF) for systematic and transparent analysis of MOA data and information. Based mainly on non-DNA-reactive carcinogens, the HRF features a “concordance” analysis of MOA information from both animal and human sources, with a focus on determining the appropriate role for each MOA data set in human risk assessment. With MOA information increasingly available for risk assessment purposes, this article illustrates the further applicability of the HRF for reproductive, developmental, neurologic, and renal endpoints, as well as cancer. Based on qualitative and quantitative MOA considerations, the MOA/human relevance analysis also contributes to identifying data needs and issues essential for the dose-response and exposure assessment steps in the overall risk assessment. [ABSTRACT FROM AUTHOR]

Assessment of risks to human health from chemical agents is a complex process that requires the assembly, careful analysis, and integration of human and animal data collected from studies performed at different times, for disparate purposes, and under varying conditions. The application of risk assessment methods to data without consideration of the relevance of critical experimental parameters such as route of exposure or magnitude of dose can lead to specious determinations of the risk posed by exposure to environmental agents. A case study of the purported risk of developmental toxicity from inorganic arsenic is presented to illustrate (1) the nature of the problem, (2) how extant data from all studies are useful, (3) how appropriately designed modern studies can clarify the situation, and (4) how conflicted data should be evaluated in terms of appropriateness for use in risk assessment. [ABSTRACT FROM AUTHOR]