Neurotoxicity assessment guidelines

Environmental Protection Agency (1991). Pesticide Assessment Guidelines Subdivision F, Hazard Evaluation Human and Domestic Animals. Addendum 10, Neurotoxicity Series... 

The series of Risk Assessment Guidelines includes a guideline for neurotoxicity risk assessment (US-EPA 1998), see Section 4.7.7.3. 

The series of Risk Assessment Guidelines includes a guideline for neurotoxicity risk assessment (US-EPA 1998). This Guideline sets forth principles and procedures to guide US-EPA scientists in evaluating environmental contaminants that may pose neurotoxic risks, and inform US-EPA decision-makers and the public about these procedures. The Guideline includes a discussion of general dehnitions and issues, an overview of test methods, and the interpretation of data within the U.S. framework for risk assessment. 

Pesticide assessment guidelines under the Federal Insecticide, Fungicide, and Rodenticide Act stipulate that organophosphates proposed for use as insecticides be tested both for their capability to cause acute toxicities due to inhibition of acetylcholinesterase and for their potential to cause inhibition of neurotoxic esterase and subsequent delayed neuropathy. Testing could be performed in laboratory rodents because they, like all species, are susceptible to acetylcholinesterase inhibition, but rodents do not develop notable ataxia, and neuropathological... 

Environmental protection Agency (EPA) Pesticide assessment Guidelines, Subdivision E. Hazard Evaluation Human and domestic Animals. Addendum 10 Neurotoxicity, Series 81, 82, and 83. National Technical Information Service, Springfield, VA, 1991. 

U.S. EPA. 1984. Pesticide assessment guidelines. Subdivision E, hazard evaluation Human and domestic animals. 1991. Pesticide assessment guidelines. Subdivision F, addendum 10. Neurotoxicity series 81, 82, and 83. 

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). 

US Environmental Protection Agency (1998) Guidelines for neurotoxicity risk assessment. Federal Register 63 26926-26954 http //www.epa.gov/raf/publications/pdfs/NEUROTOX. PDF Accessed 15 Feb 2011... 

The Neurotoxicity Screening Battery test guideline (OPPTS 870.6200) consists of a functional observational battery, motor activity, and neuropathology. The test battery is not intended to provide a complete evaluation of neurotoxicity, and additional functional and morphological evaluation may be necessary to assess completely the neurotoxic potential of a chemical. 

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. 

U.S. EPA (U.S. Environmental Protection Agency). 1995a. Proposed Guidelines fo Neurotoxicity Risk Assessment. Fed. Reg. 60 (192) 52032-52056. 

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. 

Makris SL, Raffaele K, Allen S, et al. A retrospective performance assessment of the developmental neurotoxicity study in support of OECD test guideline 426. Environ. Health Perspect. 2009 117 17-25. 

Figure 1 US governmental guidelines for study designs of developmental toxicity assessments in animal models, (a) FDA Segment I developmental toxicity study (b) FDA Segment III - perinatal and postnatal study (c) ERA developmental neurotoxicity study.

Numerous neurotoxic chemicals have been identified. These include pesticides (particularly, but not limited to, organophosphates and carbamates), aliphatic and aromatic hydrocarbons, alcohols, ethers, ketones, heavy metals (including lead, mercury, manganese, and others), and mixtures of these. Hundreds of individual chemicals are established or suspected neurotoxins. The EPA Guidelines for Neurotoxicity Risk Assessment and the Scorecard list of neurotoxicantsl5 contain partial lists of neurotoxic chemicals. The actual number of chemicals with neurotoxic potential has been estimated to range between 3% and 28% of all the approximately 80,000 chemicals in use (2400-22,400) Clearly, the number of mixtures possible is infinite, though little attention has been devoted to the neurotoxic effects of mixtures. 

USEPA (1995a) Proposed guidelines for neurotoxicity risk assessment. Fed Reg 60 52032-52056. 

S. L. Makris, K. Raffaele, S. Allen, W. J. Bowers, U. Hass, E. Alieva, G. Calamandrei, L. Sheets, P. Ameolf, N. Delrue and K. M. Crofton, A retrospeetive performance assessment of the developmental neurotoxicity study in support of OECD test guideline 426, Environ. Health Perspect., 2009, 117, 17-25. 

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