Neurodevelopment, Neurotoxicology & Neurodegenerative Diseases
The nervous system is the target organ for a wide variety of compounds. For example, lead exposure has been associated with lower intelligence scores in children and manganese (which is considered an essential nutrient), at sufficiently high exposures, has been associated with neurotoxic effects similar to those of Parkinson’s disease. Although organophosphate insecticides are designed to target the nervous system of insect pests, the signaling pathways involved are generally conserved across organisms, including humans; thus, these chemicals may also cause off-target effects in people. The toxic effects of chemicals on the brain or peripheral nervous system may have far-reaching consequences. While some neurotoxic effects are reversible, others may be longer-lasting or permanent. There is also increasing concern for the potential of chemicals and pharmaceuticals to cause more subtle neurodevelopmental effects, including autism and attention deficit disorders. Assessing the potential neurotoxic effects of agrochemical, veterinary medicine, and pharmaceutical agents following developmental or adult exposures is an important component of safety assessments.
Exponent’s toxicologists have extensive experience in the chemical and pharmaceutical industries, academia, and government and have worked on projects at the state, national, and international levels. They have practical expertise in planning, conducting and coordinating regulatory guideline-based toxicity studies and investigative human studies to address potential neurotoxicologic issues for both chemicals and pharmaceuticals. Our strong scientific expertise, practical bench laboratory experience and appreciation of different regulatory frameworks allow us to better anticipate and address potential issues that could impact risk assessment decisions. We are also proficient at interpreting study data for standard-setting and risk/safety assessment, conducting weight-of-evidence assessments regarding possible links between exposure to specific compounds and neurotoxic effects, quantitative benchmark dose analysis, and chemical risk assessment (including the need for FQPA and PCPA factors). In addition, Exponent has assisted clients in determining whether further targeted testing was needed for their compound or whether waiver requests for additional studies were appropriate based on the available data (both guideline-complaint and published studies) and in developing responses for submission to regulatory bodies.
Our scientists have considerable regulatory experience as senior scientists/directors at the US EPA and the UK Pesticides Safety Directorate, and as members of national and international expert committees. They also have been involved in developing regulatory guidelines for adult and developmental neurotoxicity. Thus, Exponent is unique in that we can bring to bear powerful multi-disciplinary expertise in industrial hygiene, molecular biology & mode-of-action, epidemiology, toxicology, and risk assessment to solving scientific problems in adult and developmental neurotoxicity (DNT).
Bal-Price AK, Coecke S, Costa L, Crofton KM3, Fritsche E, Goldberg A, Grandjean P, Lein PL, Li A, Lucchini R, Mundy WR, Padilla S, Persico AM, Seiler AEM, Kreysa J. Advancing the Science of developmental neurotoxicity (DNT): Testing for better safety evaluation. ALTEX 2012; 29:202–215.
DeSesso JM, Watson RE, Keen CL, Hazelden KP, Haws LC, Li AA. Analysis and integration of developmental neurotoxicity and ancillary data into risk assessment: A case study of dimethoate. J Toxicol Environ Health Part A 2009; 94–109.
Faber W, Kirkpatrick D, Coder P, Li A, Borghoff S, Banton M. Subchronic, reproductive, and maternal toxicity studies with tertiary butyl acetate (TBAC). Regulatory Toxicology and Pharmacology 2014; 68:332–342.
Garman RH, Li AA, Kaufmann W, Auer RN, Bolon B. Recommended methods for brain processing and quantitative analysis in rodent developmental neurotoxicity studies. Toxicol Pathol. 2015 Aug 21. pii: 0192623315596858. [Epub ahead of print].
Li, AA, Levine TE, Burns CJ, Anger WK. Integration of epidemiology and animal neurotoxicity data for risk assessment. Neurotoxicology 2012 Aug; 33(4):823–832.
Li, AA, Lowe, KA, McIntosh, LJ, Mink, PJ. Evaluation of epidemiology and animal data for risk assessment: Chlorpyrifos developmental neurobehavioral outcomes. JTEH Part B 2012; 15:109–185.
Li, AA, Fowles J, Banton M, Picut C, Kirkpatrick D. Acute inhalation study of allyl alcohol for derivation of acute exposure guideline levels. Inhalation Toxicology 2012; 24:213–226.
Li AA, Maurissen JP, Barnett JF Jr, Foss J, Freshwater L, Garman RH, Peachee VL, Hong SJ, Stump DG, Bus JS. Oral gavage subchronic neurotoxicity and inhalation subchronic immunotoxicity studies of ethylbenzene in the rat. Neurotoxicology. 2010; 31:247-58.
Li AA, Baum MJ, McIntosh LJ, Day M, Liu F, Gray LE. Building a scientific framework for studying hormonal effects on behavior and on the development of the sexually dimorphic nervous system. Neurotoxicology 2008; 29:504–519.
Li AA, Mink P, Mcintosh, LJ, Teta M, Finley B. Evaluation of epidemiologic and animal data associating pesticides with Parkinson’s Disease. J Occup Environ Med 2005; 47(10):1059–1087.
Llorens J, Li A, Ceccatelli S, Sunol C. Strategies and tools for preventing neurotoxicity: to test, to predict and how to do it. Neurotoxicology 2012 Aug; 33(4):796–804.
Mink PJ, Kimmel CA, Li AA. Potential effects of chlorpyrifos on fetal growth outcomes: Implications for risk assessment. J Toxicol Environ Health B Crit Rev 2012;15(4):281–316.
Williams, AL, and JM DeSesso. 2014. Gestational/Perinatal chlorpyrifos exposure is not associated with autistic-like behaviors in rodents. Critical Reviews in Toxicology 44:523-534.
Williams, AL and JM DeSesso. 2010. The potential of selected brominated flame retardants to affect neurological development. Journal of Toxicology and Environmental Health, Part B 13:411-448.
John M. DeSesso, Ph.D., DABFM, DABFE, FACFEI, DABCHS, Fellow ATSToxicology & Mechanistic BiologyCenter Director, Office Director & Principal ScientistAlexandria