Neurotoxicity testing: a discussion of in vitro alternatives.

Abstract

A large number of chemicals may exert adverse effects on the central and/or peripheral nervous system. A commonly recommended strategy for neurotoxicity testing is that of a tiered approach aimed at identifying and characterizing the neurotoxicity of a compound. Guidelines exist in the United States and other countries that define the tests to be utilized in tier 1 testing. To address problems related to the increasing cost and time required for toxicity testing, the increasing number of chemicals being developed, and the concern of animal welfare activists, attention is currently being devoted to in vitro alternatives. This paper addresses the use of in vitro systems in neurotoxicology, and their potential role in a general strategy for neurotoxicity testing. The advantages and disadvantages of in vitro approaches for mechanistic studies and for screening of neurotoxicants are discussed. Suggestions for further validation studies are proposed. Environ Hecalth Perspect 106(Suppi 2):505-510 (1998). 505-51Ocosta/abstract.html

An in vitro approach to assess the toxicity of certain food contaminants: Methylmercury and polychlorinated biphenyls

“…Such a battery should be seen as a Tier I approach, to be followed, in case of positive indications of neurotoxicity (as in the present case), by a series of Tier II tests in vitro exploring additional end-points of neurotoxicity (Costa, 1998;Harry et al, 1998;Stacey and Viviani, 2001;Gartlon et al, 2006). A very important step in this process would obviously be that of validation, which could initially be accomplished by testing a number of known neurotoxic and non-neurotoxic compounds to ensure specificity and rate of false positives and negatives.…”

“…Guidelines for neurotoxicity and developmental neurotoxicity testing have been developed, that require cumbersome protocols prescribed for standard tests in animals. Economical and time considerations, as well as ethical considerations for reducing the number of animals, have in recent years argued for the need to develop alternative in vitro methodologies to test for potential neurotoxicity (Costa, 1998;Harry et al, 1998;Gartlon et al, 2006). No in vitro neurotoxicity test has been fully validated so far, and regulatory agencies accept only in vivo animal data to predict potential neurotoxic effects in humans.…”

“…No in vitro neurotoxicity test has been fully validated so far, and regulatory agencies accept only in vivo animal data to predict potential neurotoxic effects in humans. Yet, in addition to their established role to investigate mechanisms of neurotoxicity, in vitro systems may be useful to screen and prioritize compounds, and to provide initial information useful to guide further in vitro and in vivo studies (Costa, 1998;Harry et al, 1998;Gartlon et al, 2006). The present study explores the possible development of a series of in vitro screening assays by focussing on three known neurotoxicants, methylmercury (MeHg) and two polychlorinated biphenyls (PCBs).…”

Screening for Developmental Neurotoxicity Using PC12 Cells: Comparisons of Organophosphates with a Carbamate, an Organochlorine, and Divalent Nickel

“…One strategy proposed to resolve this problem is the use of screening techniques based on cell culture systems or lower organisms as the first stage of evaluation, thus enabling subsequent animal studies to focus on those compounds most likely to cause developmental neurotoxicity (Costa 1998; Slotkin 2004b). This approach was recently endorsed in a report from the Inspector General of the U.S. EPA (U.S.…”

Current techniques for assessing developmental neurotoxicity of pesticides

“…A new set of test paradigms, relying on primary work in cell culture, invertebrates, or non-mammalian models, followed by more targeted examinations of specific processes in mammalian models, may unite cutting-edge academic research with the need for establishing flexible guidelines for developmental neurotoxicity [9,10]. This approach was recently endorsed in a report from the Inspector General of the U.S. EPA [5] as well as by outside groups [1,[9][10][11]. In this paper, we summarize techniques used in each stage respectively, as follows.…”