Toxicity neurotoxicity testing

European Centre for the Validation of Alternative Methods (ECVAM), six in vitro systems for chronic neurotoxicity testing are recommended for further consideration (Worth and Balls 2002). These are described as in vitro models that may be suitable for long-term toxicity testing. The systems are... 

Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test 424 Neurotoxicity study in rodents... 

The adopted test guideline methods for repeated dose toxicity testing include a number of parameters relevant for the evaluation of a substance s neurotoxic potential. Eurthermore, specific test guidelines for neurotoxicity testing have also been adopted. These test methods are addressed in Section 4.7.3.1 and Tables 4.11 and 4.12. 

The developmental neurotoxicity test (OECD TG 426 Draft, US-EPA OPPTS 870.6300) can be conducted as a separate study, incorporated into a reproductive toxicity study and/or adult neurotoxicity study, or added onto a prenatal developmental toxicity study. 

Results from these studies or other available information may trigger the need for longer term (1-year or 2-year) or specialized (e.g. reproductive/developmental toxicity, neurotoxicity, etc.) tests... 

Due to a lack of sufficient scientific evidence regarding safety, further tests are needed to evaluate geno-toxicity, reproductive toxicity, neurotoxicity, chronic and carcinogenicity. 

Most mineral oil hydraulic fluids are made from processed petroleum crude oils that are blended with various types of nonhydrocarbon additives to impart specific, use-related properties to the fluid (ATSDR 1997b). The carbon number range of hydrocarbons in hydraulic fluids varies depending on the intended application of the fluid, but mostly is in the range of C15-C 50. Toxicity data for mineral oil hydraulic fluids are restricted to acute lethality studies of rats exposed by gavage or by inhalation to several types of mineral oil hydraulic fluids, and single-dose gavage neurotoxicity tests that found no effects in chickens. 

In addition to the major" studies mentioned above, changes have occurred in the "minor studies requested for submission. Thus, for the organophosate insecticides potentiation studies were requested in the 60 s and well into the 70 s. However, since the protocol used for most of these studies range from farcical to barely acceptable, emphasis in this area has decreased. Conversely the improving knowledge in the area of delayed neurotoxicity testing has increased our requests for additional studies on those compounds which may have toxic potential in this field. 

Chronic toxicity including one-year chronic (rat) and two-year carcinogenicity (rat) was evaluated, no carcinogenicity was observed. The results of the two-generation-reproduction (rat) showed no effect on development or reproduction after ingestion and dermal exposure of clacyfos (Table 8.20). Because clacyfos is an organophosphoms compound, therefore, neurotoxicity test was additionally conducted, which was also negative (Table 8.20). 

A particular mode of neurotoxicity was discovered for tricresyl phosphate that correlated with the presence of the o-cresyl isomer (or certain other specific aLkylphenyl isomers) in the triaryl phosphates. Many details of the chemistry and biochemistry of the toxic process have been elucidated (139,140,143—146). The use of low ortho-content cresols has become the accepted practice in industrial production of tricresyl phosphate. Standard in vivo tests, usually conducted with chickens sensitive to this mode of toxicity, have been developed for premarket testing of new or modified triaryl phosphates. As of 1992, the EPA called for extensive new toxicity and environmental data on this group of products (147). The Vederal e ster AoQ xm. ci. calling for this... 

Short- to medium-term exposure has shown neurotoxicity, developmental toxicity, immunotoxicity, and endocrine disruption to be relevant end-points. Table 24 summarizes the critical studies for each compound and identifies NOAELs or LOAELs. The degree of each of the toxic end-points differs across the group as a whole. For example, tributyltin is well established as an aromatase inhibitor, and dibutyltin appears to have some potency also (exact characterization of the endocrine disrupting capacity of dibutyltin alone is difficult because of the presence of tributyltin as an impurity). Monobutyltin and mono- and dioctyltins have no aromatase inhibiting capacity in in vitro tests. No data are available for this end-point for the methyltins. 

In summary, neurotoxic effects of endosulfan are usually apparent only after acute ingestion of relatively high doses. Cumulative neurotoxicity does not appear to be significant. If the animal survives the acute toxic effects, then no long-term neurotoxic effects are evident from behavioral, gross, and microscopic observations. However, some impairment may occur that can be detected only by specialized neurobehavioral testing. 

---