The Maximum Tolerated Dose for Inhalation Bioassays: Toxicity vs Overload

A 1973 workshop sponsored by the National Cancer Insti-other hand, particles of high intrinsic toxicity, e.g., quartz and mineral fibers, may induce similar adverse effects at tute led to the establishment of guidelines for carcinogenicity testing which included the maximum tolerated dose (MTD) much lower exposure levels and retained lung burdens without evidence of dust overload.defined as the highest dose used in a chronic study that can be predicted not to alter the animal's normal longevity from Possible interactive relationships between retained particles and lung tissue that are fundamental to MTD considera-effects other than carcinogenicity (Sontag et al., 1976).From the perspective of the inhalation toxicologist, the tions are schematically portrayed in Fig. 1.This depiction of the responses and effects of low and high particle burdens MTD definition might be modified as describing the highest exposure level recommended for a chronic inhalation study provides a hypothetical pathogenic sequence.At high dust burdens of poorly soluble particles of low cytotoxicity (and eliciting signs of minimal toxicity without significantly decreasing the animal's life span.This exposure level is deter-with toxic lower burdens of particles) a dose-related pulmonary inflammatory response and depressed alveolar particu-mined primarily by prechronic inhalation study findings.In general, the MTD is expected to provide maximal opportu-late clearance develop which, if persistent and sufficiently intense, can progress to fibrosis and/or tumors.Under condi-nity for the detection of carcinogenic potential and, with additional exposure levels, provide exposure-response and tions of particle overload, tumor induction primarily by nongenotoxic particles may be dominant.exposure-effect data for risk assessment.The 1995 SOT Workshop on the Maximum Tolerated The following summaries of workshop presentations provide a historical introduction to the use of the MTD, Dose in the Lung addressed the difficulties surrounding the setting of the highest exposure levels in chronic inhalation describe the problems of exposure and animal selection, examine the mechanistic bases for particulate-induced in-studies of particulate materials, where many of the adverse effects usually signifying the MTD are not deemed appro-flammatory responses and long-term pathologic effects in the lungs, and review diverse chronic inhalation study priate.Moreover, lung tumors have occurred in rats chronically exposed to high concentrations of insoluble dusts which findings from both the investigative and regulatory perspectives relative to the MTD.are generally considered to be benign, e.g., carbon black and titanium dioxide.These tumors are believed to be secondary to excessive lung dust burdens, i.e., particle overload, and, THE MTD: A HISTORICAL PERSPECTIVE consequently, are both confounding and indicative that the (J.K. Haseman) MTD in the lung has been substantially exceeded.On the In the late 1960s the National Cancer Institute (NCI) be-The U.S. Government's right to retain a nonexclusive royalty-free license gan evaluating chemicals for possible carcinogenic effects in and to the copyright covering this paper, for governmental purposes, is in laboratory rodents.The primary objective of these bioasacknowledged.says was to screen chemicals for carcinogenic potential, and 1 Workshop held at the 34th Annual Meeting of the Society of Toxicology doses were selected to maximize the likelihood of detecting (SOT) in Baltimore, MD, sponsored by the Inhalation Specialty Section of a rodent carcinogen.These experiments generally used two SOT.2 To whom reprint requests should be addressed.doses: the maximum tolerated dose (MTD) and 1/2 MTD.