Evaluation of developmental toxicity data: a discussion of some pertinent factors and a proposal.

There is currently no well-accepted standard method for evaluation of developmental toxicity data. This paper presents one approach to the evaluation of developmental toxicity data. We initially identify some pertinent factors that influence the interpretation of animal data and summarize the literature pertaining to these factors. Such factors include the quality and quantity of data and the relationship between maternal and developmental toxicity. We proceed with a discussion of quantitative assessment of data and propose schemes for qualitative and quantitative developmental hazard assessments.

Methylene chloride mortality study: dose-response characterization and animal model comparison.

To assess the potential chronic health effects of methylene chloride, the mortality experience of a maturing 1964 to 1970 cohort of 1,013 hourly men was evaluated through 1984. On average, employees were exposed at a rate of 26 ppm (eight-hour time-weighted average) for 22 years; median latency was 30 years. Compared with the general population, no statistically significant excesses were observed for such hypothesized causes as lung cancer (14 observed v 21.0 expected), liver cancer (0 v 0.8), and ischemic heart disease (69 v 98.1); dose-response relationships based on career methylene chloride exposure and latency were not demonstrated. Among nonhypothesized causes, a significant deficit was reported for total deaths (176 v 253.2). None of the industrial referent comparisons achieved statistical significance. Sufficient power was available to detect relative risks of 1.6 for lung malignancy and 1.3 for ischemic heart disease. In contrast, there was inadequate power to identify meaningful risk levels for hepatic cancer. With 14 combined lung and liver cancer deaths observed v 36.3 predicted (P less than .0001), the mortality estimate projected from a mathematical model derived from an animal bioassay substantially overestimated cancer mortality for these sites. This inconsistency emphasizes the need to incorporate epidemiologic evidence in assessing the human health risks associated with long-term exposure to this widely used solvent.

Toxic neuropathy--an overview.

The involvement of the nervous system in systemic intoxication offers diagnostic and investigative challenges to the occupational health team. Often early evidence of neurotoxicity is vague, of a highly subjective nature and may be complicated by the presence of neuropathies due to other causes such as diabetes mellitus or exposure to multiple neurotoxins such as lead and solvents. The variety of agents producing neurotoxicity is wide, including heavy metals, organophosphates, acrylamide and its analogs, industrial solvents, therapeutic agents and plant alkaloids. The identification of neurotoxic substances requires well controlled epidemiologic studies of humans, including electrodiagnostic testing and well planned experimental animal studies. The latter include consideration of choice of animal species, routes of administration, duration of exposure, clinical evaluation, electrodiagnostic testing, morphologic description of the damage produced and its distribution, and the recognition of the potential for intercurrent naturally occurring neuropathologic processes. The aim of this discussion is to give an overview of these and other factors involved in the assessment of a neurotoxic potential.

Nervous system degeneration produced by the industrial solvent methyl n-butyl ketone.

Because of a number of cases of peripheral neuropathy that occurred in factory workers employed in a fabric-printing plant in 1973, chronic inhalation experiments have been conducted using the printing-ink solvents methyl n-butyl ketone (MBK) and methyl iso-butyl ketone (MIBK). After four months of intermittent respiratory exposure to 1,300 parts per million (ppm) MBK, all six rats tested developed severe symmetric weakness in the hindlimbs. Morphological studies showed massive focal axonal enlargements containing abnormally large numbers of neurofilaments and dying-back axonal degeneration in peripheral and central nerve fibers. Six rats similarly exposed for five months to 1,500 ppm of MIBK showed minimal distal axonal change, but remained neurologically intact. The principal conclusion of this study is that MBK is a neurotoxin in rats.