Risk assessment developmental neurotoxicity

Davis MJ. 1990. Risk assessment of the developmental neurotoxicity of lead. Neurotoxicology 11 285-292. 

Often several different toxic hazards (neurotoxicity, organ toxicity, developmental toxicity, for example) associated with the substance that is the subject of the risk assessment, each with its own dose-response characteristics, will emerge from the first two steps of the risk assessment. Which of these should become the principal basis for the final risk assessment. ... 

The developmental neurotoxicity guideline, accepted by OECD in 2007, has added the important aspect of behavioral effects of pre- and postnatal exposure to chemicals. This development arose from the notion that behavioral disorders in man such as anxiety, depression, phobias, autism, and attention deficit hyperactivity disorder, which appear to show increasing prevalences in western societies, may have a perinatal origin (4, 5). In the absence of causal inferences with respect to chemicals it seems nevertheless prudent to assess in a risk assessment whether such causal relations may exist. 

In a few cases, studies to evaluate developmental neurotoxicity or other postnatal functions may have been conducted, and these can provide amore complete evaluation of potential developmental effects. In addition to the standard guideline studies, data from experimental studies on mechanisms of action, etc., can provide useful data for consideration in the risk assessment process. 

With respect to the hazard identification part of the risk assessments, the main uncertainties discussed in these documents relate to the human health relevance of the observed developmental neurotoxicity in rodents. These are uncertainties that have been highlighted in all three documents. Likewise, the predicted no effect concentration for contaminated sediments is considered uncertain in all three risk assessments. The predicted no-effect concentration (NOEC) for water is considered uncertain for Octa and Deca, and the predicted no-effect concentration for the terrestrial compartment is identified as uncertain for Octa. 

European Commission 2003a). However, the risk assessors seem to be more reluctant to use this default assumption to assess the relevance of the observed indications of developmental neurotoxicity in rodents. For this endpoint additional data are requested. 

Some of these side effects may be impossible to detect either in vivo or using alternative model systems nevertheless, the availability of models that would be predictive of neurotoxic effect is of great relevance for the risk assessment of existing chemicals and of new molecular entities. In vivo testing guidelines for neurotoxicity and developmental neurotoxicity have been developed, implemented, and validated. Though there is still room for improvements and refinements, these in vivo tests have been shown, so far, to provide reliable indications on the potential neurotoxicity of chemical substances. However, such in vivo tests are time consuming and expensive and require the use of a substantial number of animals. 

Cory-Slechta DA, Crofton KM, Foran JA, et al. Methods to identify and characterize developmental neurotoxicity for human health risk assessment. I Behavioral effects. Environ Health Perspect. 109(Suppl. 1) 79—91. 

Hass U (2006) The need for developmental neurotoxicity studies in risk assessment for developmental toxicity. Reprod Toxicol 22 148-156... 

Dorman, D., Allen. S Byezkowski, J., Claudio, L., Fisher, J. I., Fisher, L, Harry, G., Li, A, Makris, S., Padilla, S., Sultatos, L., and Milcson, B. (2001). Methods to identify and characterize developmental neurotoxicity for human health risk assessment. Ill Pharmacokinetic and pharmacodynamic considerations. Environ. Health Perspect. 109,101-111. 

CMs include AChE inhibition, particularly in the blood and brain behavioral and/or motor activity changes and developmental toxicity or developmental neurotoxicity. When EPA evaluates AChE data for risk assessment purposes, measurements of AChE from the target tis.sue — the central or peripheral nervous system — are preferred. Toxicology studies submitted to EPA for pesticide registration typically measure plasma, red blood cell (RBC), and brain cholinesterase (ChE) inhibition and most often do not measure peripheral tissues. In the absence of such data, EPA considers blood measures as surrogate.s of peripheral tissues,... 

FQPA requires that EPA apply a lOX factor to account for added sensitivity of infam.s and children unless there are sufficient data to reduce this factor. This factor is called the FQPA lOX factor for the protection of infants and children. In single-chemical risk assessments, EPA-OPP evaluates the adequacy of the toxicology database for evaluating potential sensitivity in infants or children on a chemical-by-chemical basis, EPA publi.shcd a data-call in notice (DC ) requiring developmental neurotoxicity (DNT) studies for each of the OPs with active pesticide regi,straiions. In addition to the DNT study, a companion... 

Carbary E Caibofjran 1 10 100 Maternal alterations in FOB were seen or the first day of dosing and ChE inhibition Risk assessment not complete Rat Developmental neurotoxicity 0.01... 

Evaluation and interpretation of the DNT and comparative cholinesterase study data are conducted in accordance with agency risk assessment guidelines for developmental toxicity, reproductive toxicity, and neurotoxicity (EPA, 1991b, 1996, 1998e). Risk as.se.ssinents. including determination of reference values and application of traditional uncertainty factors in the calculations, are conducted ba.sed on historically established principles (NAS, 1983). 

Buelke-Sara. J., and Maetiuus, C. K (1990). Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxiciiy. Work Group II repon Testing methods in developmental neurotoxicity for use in human risk assessment. Neurotoxicoi TeraU>i 12(3), 269-274. 

None of the new studies on nephrotoxicity, developmental toxicity, neurotoxicity or immunotoxicity that have appeared since the Committee s last evaluation would have an impact on the Committee s previous selection of minimal renal changes in the pig, observed at a dose of 8 pg/kg bw per day (the LOEL), as a critical effect for risk assessment. 

The overall schematic for quantified health risk estimates in the analysis of U.S. EPA (2007) entailed combining concentration—response functions with blood lead distributional statistics generated for each of the three case studies to produce distributions of IQ loss estimates for each study population. Before the quantitative analyses of health risk were done via using differing concentration—response functions, the health risk portion in U.S. EPA s full-scale health risk assessment was evaluated to produce several statistical modeling and assessment steps for the risk metric, IQ point loss, in young children sustaining developmental neurotoxicity effects at various PbB estimates. 

See also Androgens Developmental Toxicology Dose-Response Relationship Endocrine System Levels of Effect In Toxicological Assessment Neurotoxicity Radiation Toxicology, Ionizing and Nonionizing Reproductive System, Female Reproductive System, Male Risk... 

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