Neurotoxicity, prediction

Goldey ES, Tilson HA, Crofton KM. 1995. Implications of the use of neonatal birth weight, growth, viability, and survival data for predicting developmental neurotoxicity A survey of the literature. Neurotoxicol Teratol 17(3) 313-332. 

The data in animals are insufficient to derive an acute inhalation MRL because serious effects were observed at the lowest dose tested (Hoechst 1983a). No acute oral MRL was derived for the same reason. The available toxicokinetic data are not adequate to predict the behavior of endosulfan across routes of exposure. However, the limited toxicity information available does indicate that similar effects are observed (i.e., death, neurotoxicity) in both animals and humans across all routes of exposure, but the concentrations that cause these effects may not be predictable for all routes. Most of the acute effects of endosulfan have been well characterized following exposure via the inhalation, oral, and dermal routes in experimental animals, and additional information on the acute effects of endosulfan does not appear necessary. However, further well conducted developmental studies may clarify whether this chemical causes adverse developmental effects. 

Although the effects of chronic exposure of humans to low levels of POPs are difficult to predict, some biological effects have been described. For example, exposure of children to PCBs and PCDD/Fs may be linked to an elevated risk for infectious diseases. Exposure of pregnant women to PCDD/Fs may cause lower fertility in their male offspring. The adverse effects to human health of acute and chronic exposure of high concentrations of POPs, especially among industrial workers exposed to daily intakes of chemicals, are more evident. Elevated concentrations of DDE and TCDD have been associated with the development of cancers such as breast cancer, leukaemia and thyroid cancer. Dioxin exposure may also be associated with immunotoxicity, reproductive diseases and neurotoxicity. Extreme exposure to chlorinated compounds has resulted in death [101]. 

If the neurotoxicity of /7-hexane was potentiated in this study by co-exposure to acetone, the level of n-hexane alone required to produce these effects would be higher than 58 ppm and the MRL level would be higher. Results from simulations with a PBPK model that accurately predicted /7-hexane blood and 2,5-hexanedione urine levels (Perbellini et al. 1986, 1990a) indicate that at concentrations of 50 ppm, the rate-limiting factor in /7-hexane metabolism is delivery to the liver, not metabolic activity. This suggests that at this concentration (and at the MRL concentration of 0.6 ppm), induction of P-450 enzymes in the liver by acetone or other chemicals would not affect the rate at which 2,5-hexanedione was produced. 

Comparative Toxicokinetics. The toxicokinetic studies available indicate that the rat is a good model for human neurotoxicity observed after occupational exposure to 77-hexane. Mild signs can be produced in chickens and mice, but these do not progress to the serious neurotoxicity observed in humans and rats. Toxicokinetic data from other species (absorption, distribution, metabolism, excretion) could provide insight on the molecular mechanism(s) of the species specificity of 77-hexane toxicity and would be valuable for predicting toxic effects in humans. 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

Bondy, S.C. (1979). Rapid screening of neurotoxic agents by in vivo means. In Effects of Food and Drugs on the Development and Function of the Nervous System Methods for Predicting Toxicity. Gryder, R.M. and Frankos, VFL, (Eds.) Office of Health Affairs, FDA, Washington, D.C., pp. 133-143. 

In an attempt to find an in vitro assay to predict differences in the neurotoxic potential of bisindole alkaloids, an assay using cultured rat midbrain cells was developed. This system provided a qualitative measure of the effect of compounds on neuronal tissue, and when several compounds (for which clinical toxicity data were available) were evaluated using this method the results were consistent in rank order with the compounds clinical manifestation of neurotoxicity. When vinepidine was studied in this system, it was found to produce a minimal effect (Fig. 7). 

In conclusion, recent evidence suggests that MDMA and related compounds do not deserve the widespread belief that they are harmless substances which should be legally available. They constituted a potentially serious risk for acute toxic reactions that cannot be predicted by the dose taken. The acute reactions carry with them significant mortality and morbidity while the neurotoxicity shown to occur in rodents, primates and now in man suggests that they have a potential to cause permanent brain damage. 

While animal studies are used for safety assessment prior to administration to humans, preclinical testing may not always predict human effect. For example, continuous-infusion therapy with 260F9 monoclonal antibody-recombinant ricin A chain resulted in severe neurotoxic effects in humans that were not demonstrated in monkey toxicology studies [21], In such cases where suitable animal models are not available for safety testing it is important to consider the application of an appropriate safety factor to provide a margin of safety for protection of humans receiving the initial clinical dose [11,18]. 

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. 

The number of useful biomarkers to predict neurotoxicity, hepatotoxicity or cardiovascular toxicity is still rather limited and they are not yet well established as tools in pharmaceutical laboratories. Even though some decent correlations between biomarkers and toxicological events have been demonstrated, " a significant amount of validation work still has to be performed. Eor example, while natriuretic peptides and troponin can be clinical markers for cardiovascular toxicity, preclinical use in... 

Lotti, M. and M.K. Johnson. 1978. Neurotoxicity of organophosphorus pesticides predictions can be based on in vitro studies with hen and human enzymes. Arch. Toxicol. 41 215-221. (Cited in Munro et al., 1994 )... 

Malygin, V.V., Sokolov, V.B., Richardson, R.J., Makhaeva, G.F. (2003). Quantitative structure-activity relationships predict the delayed neurotoxicity potential of a series of O-alkyl-O-methylchloroformimino phenylphosphonates. J. Toxicol. Environ. Health Part A 66 611-25. 

Richardson, R.J., Dudek, B.R. (1983). Neurotoxic esterase characterization and potential for a predictive screen for exposure to neuropathic organophosphates. In Pesticide Chemistry Human Welfare and the Environment, Vol. 3 (J. Miyamoto, P.C. Kearney, eds), pp. 491-5. Pergamon Press, Oxford. 

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