Willard R. Chappell

Neurobehavioral test methods for environmental health studies of adults

The Agency for Toxic Substances and Disease Registry convened a workshop in Atlanta, GA, that evaluated approaches and methods to ascertain whether there are neurobehavioral sequelae to children and adults exposed to hazardous substances in the environment. This article, developed from that Workshop, recommends testing methods [to identify neurotoxic insult] for immediate use in environmental health field studies of adults. A list of broad functional domains or modalities affected by chemicals was identified from the occupational and related literature (learning and memory, coding, sustained attention, higher intellectual function, strength, coordination, speed, vision, somatosensory, and affect). A core set of tests was selected that should assess those functions with the greatest demonstrated sensitivity to established neurotoxic chemicals, and a secondary set was selected to assess a broader group of functions. The core tests should be used in all investigations where neurotoxic effects would be targeted for identification; secondary tests would be used where suggested by questionnaire or symptom data or by knowledge of the effects of chemicals at the hazardous waste site.

Does the animal-to-human uncertainty factor incorporate interspecies differences in surface area?

Risk assessment practices for noncarcinogens typically employ an uncertainty factor (UF) for animal-to-human extrapolation when defining acceptable levels for humans based on animal studies. EPA has interpreted the use of this factor as addressing interspecies differences due to dose normalization via surface area (exposure-dose relationships) and to innate differences in species susceptibility (dose-response relationships). Thus EPA has concluded that dose normalization via surface area is not necessary when using animal studies to define acceptable levels for noncarcinogens for humans. In this report we challenge this position on both theoretical and practical grounds. It is recommended that the UF for animal-to-human extrapolation for noncarcinogens in the risk assessment process and the technique for dose normalization be considered distinctly.

Neurobehavioral test strategies for environmental exposures in pediatric populations

The Agency for Toxic Substances and Disease Registry convened a workshop in Atlanta, GA, that evaluated approaches and methods to ascertain whether there are neurobehavioral sequelae to children and adults exposed to hazardous substances in the environment. This article, developed from that workshop, addresses the feasibility of employing extant neurobehavioral tests to screen pediatric populations. A matrix lists basic functions to be assessed during eight developmental periods ranging from birth to high school. The best of these neurobehavioral tests for pediatric populations and the types of assessment tools that are still needed are discussed. We make 10 specific recommendations to establish a hazardous substances neurobehavioral screen for pediatric populations, including appointing a review panel, developing a structured questionnaire, convening a conference on design and analysis, addressing minority and socially disadvantaged populations, coordinating adult and child assessment methods, information sharing among Federal agencies, baseline data, methodology research, research associated with hazardous worksites, and establishment of a pediatric databank.

Criteria for progressive modification of neurobehavioral batteries

Six specific issues affecting the progressive modification of neurobehavioral test batteries used in field studies of populations exposed to neurotoxicants are discussed and test review recommendations are provided addressing each issue. The issues include: (a) general test review standards, (b) comprehensive assessment, (c) tailored batteries, (d) incorporation of new tests and techniques, (e) personnel and mechanisms for review, and (f) development of a battery assessing peripheral nervous system function.

Adoption of an adult environmental neurobehavioral test battery

Nationally recognized experts participated in a 3-day workshop to discuss the complex issues associated with neurobehavioral testing in environmental health settings, and to propose basic and focused test batteries for use in evaluating populations living near hazardous chemical sites. The Adult Environmental Neurobehavioral Test Battery (AENTB), which evaluates major neurobehavioral domains and functions, was adopted by the Agency for Toxic Substances and Disease Registry (ATSDR) for use as a basic screening panel in field studies. Pilot testing of the AENTB demonstrated an examiner training requirement of 3-6 practice sessions, a mean total testing time of 58.0 min (SD = 9.6), and, for 9 of the component tests, a sample size requirement of fewer than 140 (alpha = 0.05, 95% power) to detect a 20% difference between study groups. ATSDR administered the AENTB to 467 persons, selected randomly from 1,382 participants in field study sites in three states. Total testing time varied noticeably by participant age and study site, suggesting an ongoing need for site-specific controls in each field study using the AENTB. Also planned is adoption of a pediatric test battery to evaluate the domains and functions most relevant at major stages of child development.

Scaling toxicity data across species

The response of various species to doses of chemicals can often give the impression that some (such as cattle in the case of molybdenum) are much more susceptible than others to these chemicals. These impressions usually rely on an underlying assumption that equivalent doses are based on mg of the chemical per kg body weight of the animal. That is, that doses scale as the first power of body weight. This assumption is more often wrong than right. When viewed in a more general way, where the scaling is proportional to a power of the body weight and the exponent determined empirically, it is often found that equivalent doses scale with an exponent in the range of 0.6 to 0.8. As a result, larger animals are indeed more susceptible to toxicity on a mg kg−1 body weight basis, but this is not because of unique differences in the species, but only because of different body sizes. This method of scaling is called allometry or allometric scaling. An early version of this approach was based on body surface area where the exponent is 2/3. More recently, pharmacokinetics has revealed that the reason for the different response of larger animals is related to the slower metabolic and clearance rates for larger animals which give rise to larger biological half-lives for chemicals in the body and to higher tissue concentrations per given dose.

Use of Risk Assessment Methodologies for Sewage Sludge Disposal Regulations

The US EPA published Part 503, Comprehensive Sewage Sludge Regulations (Federal Register, February 6, 1989) based on risk assessment methodologies to protect public health and the environment from any “reasonably anticipated adverse effects.” The sludge disposal practices are grouped into (1) agricultural land application, (2) non-agricultural land application, (3) distribution and marketing, (4) landfilling, and (5) incineration. The aggregate risk analysis results indicated that the disposal by incineration dominated the estimated health effects in terms of the annual cancer cases, number of persons crossing non-cancer exposure thresholds, and expected health impairment cases from exposures above the thresholds (primarily from lead). Unfortunately, the regulatory options proposed by EPA are not based on the methodology used for aggregate risks. Instead, the management of this disposal practice would be governed by cancer MEI (most exposed individual), reference dose for non-carcinogens, drinking water maximum concentration limits and bizarre ecosystem measures. The use of risk screening methodologies to develop risk-based management methods is inappropriate. The use of inconsistent methodologies and conservative assumptions for cases with and without supporting data indicate shortcomings. Improved methods are suggested, including approaches to avoid bizarre scenarios based on the MEI. Improvements to the methodologies with appropriate treatment of uncertainties are needed for risk-based regulations to avoid a shift in disposal practices that increase the human health risks in the US for sewage sludge disposal.