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Approaches to extrapolating animal toxicity data on organic solvents to public health.
Neurotoxicology. 2007 Mar; 28(2):221-6.N

Abstract

Synthesizing information about the acute neurotoxicity of organic solvents into predictive relationships between exposure and effect in humans is difficult because (1) data are usually derived from experimental animals whose sensitivity to the chemical relative to humans is unknown; (2) the specific endpoints measured in laboratory animals seldom translate into effects of concern in humans; and (3) the mode of action of the chemical is rarely understood. We sought to develop approaches to estimate the hazard and cost of exposure to organic solvents, focusing on the acute behavioral effects of toluene in rats and humans. Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data suggested that a 10% change in rat avoidance behavior occurs at a blood concentration of toluene 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. In contrast, our in vitro studies of nicotinic acetylcholine receptors indicated that human and rat receptors do not differ in sensitivity to toluene. Analysis of other dose-response relationships for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific endpoints measured in the two species rather than by inherent differences in sensitivity to toluene. We also explored the hypothesis that dose-equivalence relationships may be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs are estimatable, may be used as a benchmark effect for estimating the monetary benefits of controlling exposure to organic solvents. This dose-equivalence method is applicable for solvents because this set of data fulfills three important assumptions about equivalence relationships based on a single effect: (1) a common dose metric (concentration of the chemical in the brain); (2) a common effect to provide a linking variable (choice reaction time); and (3) a common mode of action (interference with neuronal ion channel function).

Authors+Show Affiliations

Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. bushnell.philip@epa.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

16684563

Citation

Bushnell, Philip J., et al. "Approaches to Extrapolating Animal Toxicity Data On Organic Solvents to Public Health." Neurotoxicology, vol. 28, no. 2, 2007, pp. 221-6.
Bushnell PJ, Boyes WK, Shafer TJ, et al. Approaches to extrapolating animal toxicity data on organic solvents to public health. Neurotoxicology. 2007;28(2):221-6.
Bushnell, P. J., Boyes, W. K., Shafer, T. J., Bale, A. S., & Benignus, V. A. (2007). Approaches to extrapolating animal toxicity data on organic solvents to public health. Neurotoxicology, 28(2), 221-6.
Bushnell PJ, et al. Approaches to Extrapolating Animal Toxicity Data On Organic Solvents to Public Health. Neurotoxicology. 2007;28(2):221-6. PubMed PMID: 16684563.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Approaches to extrapolating animal toxicity data on organic solvents to public health. AU - Bushnell,Philip J, AU - Boyes,William K, AU - Shafer,Timothy J, AU - Bale,Ambuja S, AU - Benignus,Vernon A, Y1 - 2006/03/28/ PY - 2005/10/13/received PY - 2006/03/10/accepted PY - 2006/5/11/pubmed PY - 2007/8/22/medline PY - 2006/5/11/entrez SP - 221 EP - 6 JF - Neurotoxicology JO - Neurotoxicology VL - 28 IS - 2 N2 - Synthesizing information about the acute neurotoxicity of organic solvents into predictive relationships between exposure and effect in humans is difficult because (1) data are usually derived from experimental animals whose sensitivity to the chemical relative to humans is unknown; (2) the specific endpoints measured in laboratory animals seldom translate into effects of concern in humans; and (3) the mode of action of the chemical is rarely understood. We sought to develop approaches to estimate the hazard and cost of exposure to organic solvents, focusing on the acute behavioral effects of toluene in rats and humans. Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data suggested that a 10% change in rat avoidance behavior occurs at a blood concentration of toluene 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. In contrast, our in vitro studies of nicotinic acetylcholine receptors indicated that human and rat receptors do not differ in sensitivity to toluene. Analysis of other dose-response relationships for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific endpoints measured in the two species rather than by inherent differences in sensitivity to toluene. We also explored the hypothesis that dose-equivalence relationships may be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs are estimatable, may be used as a benchmark effect for estimating the monetary benefits of controlling exposure to organic solvents. This dose-equivalence method is applicable for solvents because this set of data fulfills three important assumptions about equivalence relationships based on a single effect: (1) a common dose metric (concentration of the chemical in the brain); (2) a common effect to provide a linking variable (choice reaction time); and (3) a common mode of action (interference with neuronal ion channel function). SN - 0161-813X UR - https://www.unboundmedicine.com/medline/citation/16684563/Approaches_to_extrapolating_animal_toxicity_data_on_organic_solvents_to_public_health_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0161-813X(06)00082-9 DB - PRIME DP - Unbound Medicine ER -