The Cumulative Risk Assessment of Hepatotoxic Chemicals: A Hepatic Histopathology Perspective.

The increased concern on the consequence of exposure to multiple chemical combinations has led national regulatory authorities to develop different concepts to conduct risk assessments on chemical mixtures. Pesticide residues were identified as "problem formulation" in the respective European regulations and in this context, the European Food and Safety Authority has suggested to group pesticidal active ingredients (AIs) into cumulative assessment groups (CAGs) based on the toxicological properties of each AI. One proposed CAG, on the liver, currently consists of 15 subgroups, each representing a specific hepatotoxic effect observed in toxicity studies. Dietary cumulative risk assessments would then have to be conducted assuming dose additivity of all members of each CAG subgroup. The purpose of this publication is to group AIs based upon the knowledge of the pathogenesis of liver effects to discriminate between primary end points (direct consequence of chemical interaction with a biological target) and secondary end points (which are a consequence of, or that arise out of, a previous pathological change). Focusing on the relevant primary end points strengthens and simplifies the selection of compounds for cumulative risk assessment regarding the liver and better rationalizes the basis for chemical grouping. Relevant dose additivity is to be expected at the level of the primary/leading pathological end points and not at the level of the secondary end points. We recognize, however, that special consideration is needed for substances provoking neoplasia, and this category is included in the group of primary end points for which chemicals inducing them are grouped for risk assessment. Using the pathological basis for defining the respective CAGs, 6 liver subgroups and 2 gallbladder/bile duct groups are proposed. This approach simplifies the cumulative assessment calculation without obviously affecting consumer safety.

Approaches for grouping of pesticides into cumulative assessment groups for risk assessment of pesticide residues in food.

The European Food Safety Authority (EFSA) is developing approaches to cumulative risk assessment of pesticides by assigning individual pesticides to cumulative assessment groups (CAGs). For assignment to CAGs, EFSA recommended to rely on adverse effects on the specific target system. Contractors to EFSA have proposed to allocate individual pesticides into CAGs relying on NOAELs for effects on target organs. This manuscript evaluates the assignments by applying EFSAs criteria to the CAGs "Toxicity to the nervous system" and "Toxicity to the thyroid hormone system (gland or hormones)". Assignment to the CAG "Toxicity to the nervous system" based, for example, on neurochemical effects like choline esterase inhibition is well supported, whereas assignment to the CAG "Toxicity to the thyroid hormone system (gland or hormones)" has been based in the examined case studies on non-reproducible effects seen in single studies or on observations that are not adverse. Therefore, a more detailed effects evaluation is required to assign a pesticide to a CAG for a target organ where many confounders regarding effects are present. Relative potency factors in cumulative risk assessment should be based on benchmark doses from studies in one species with identical study design and human relevance of effects on specific target organs should be analyzed to define minimal margins of exposure.

Residues of persistent organic pollutants (POPs) in human milk in Hong Kong.

Data on pesticide body load in the south China region are scarce. Here, we report the concentrations of 24 persistent organic pollutants (POPs), in 10 pools of human milk samples, collected at 2-6weeks postpartum from 238 primiparous women living in Hong Kong and south China, who participated in the 2002-2003 WHO exposure study. Residues were determined by gas chromatography with electron capture detector and confirmed by gas chromatography with mass spectrometry. The mean levels of alpha-HCH (mean 0.6ngg(-1) fat), beta-HCH (940ngg(-1) fat), gamma-HCH (1.8ngg(-1) fat), dieldrin (1.0ngg(-1) fat) and HCB (21.8ngg(-1) fat) were much lower than the 1985 estimates. Mean levels of alpha-HCH, gamma-HCH, dieldrin, cis-heptachlor-epoxide (0.7ngg(-1) fat), sum-chlordane (6.1ngg(-1) fat), trans-nonachlor (12.0ngg(-1) fat), BDE 47 (1.9ngg(-1) fat) and sum PBDE (3.4ngg(-1) fat) were comparable to the international median levels of the 15 other countries participating in the 2002-03 WHO exposure study. Hong Kong had the highest level of beta-HCH, possibly a residual effect of previous high exposures in the 1970s. Body loads of beta-HCH and chlordane were lower among mothers with younger age while mothers born in mainland China had lower levels of beta-HCH, cis-heptachlor-epoxide, oxy-chlordane and trans-nonachlor. Levels of toxaphene, endrin, endosulfan, bromcyclene and nitrofen were not detected in all or almost all of the milk pools. Continuous monitoring of POPs in human milk, especially beta-HCH, is needed for surveillance and interpretation of time trends, and for linkage to strict enforcement of agricultural regulations.