Carol J. Henry

Correlation of inducibility of aryl hydrocarbon hydroxylase with susceptibility to 3-methylcholanthrene-induced lung cancers

C57BL/6Cum, DBA/2Cum, first filia (F1), and backcross progeny from these 2 parental strains of mice were evaluated for their susceptibility to 3-methylcholanthrene-induced lung cancers. In the crosses among these mice, aryl hydrocarbon hydroxylase (AHH) responsiveness segregated as a single autosomal dominant gene (the Ah locus). AHH responsive mice (Ahb allele) expressed 40-60 units AHH activity/g wet wt liver following intraperitoneal treatment with 3-methylcholanthrene (MCA) compared to AHH non-responsive mice (Ahd allele) which expressed 7-11 units AHH activity/g wet wt liver after MCA treatment. Intratracheal administration of 500 microgram MCA for a total of 4 times at weekly intervals yielded a variety of pulmonary cancers, including squamous cell carcinomas, alveolar adenocarcinomas, and adeno-squamous cell carcinomas among mice that survived 1 year after the carcinogen treatment. The AHH responsive C57BL/6Cum, F1, and C57BL/6Cum X F1 animals were much more susceptible to MCA-induced lung cancers than the AHH non-responsive DBA/2Cum mice. The lung cancers were also not randomly distributed in DBA/2Cum X F1 backcross progeny since significantly more lung cancers were found in AHH-responsive progeny than in AHH non-responsive mice. Data support genetic linkage between susceptibility to MCA-induced lung carcinomas and the Ahb allele.

Increased sister-chromatid exchange in bone-marrow cells of mice exposed to whole cigarette smoke

Using defined cigarette smoke exposure conditions, BC3F1/Cum mice were exposed nose-only to two different types of whole cigarette smoke on a daily basis for 1 week and up to 46 weeks. The number of sister-chromatid exchanges (SCEs) per metaphase was determined in bone-marrow cells. Studies were scheduled so that all cytogenetic observations were made 2-3 days after the last smoke exposure. Exposure to either type of smoke on a daily basis for 1 week or up to 46 weeks resulted in a 2-fold increase in SCEs over sham-exposed control mice. In animals exposed either chronically or for 1 week to either type of smoke, the increase in SCEs persisted for at least 1 week after cessation of smoke exposure. This is the first demonstration of the induction of SCEs in laboratory animals that have been exposed to cigarette smoke in vivo.

Distinguished Service Award: Evolution of Toxicology for Risk Assessment

The science of toxicology has served society well in protecting public health and the environment. Governments, the industrial sector, and the public have relied on toxicology as the foundation to assess risks to both human and ecological populations from environmental factors, including chemicals, biologic agents, physical agents, and other stressors. To maintain its prominence, the science and practice of toxicology will need to embrace the revolution underway in biology. Systems biology and biotechnologies derived from sequencing of the human genome, referred to as “genomics,” have created exciting possibilities for application to human health and environmental risk assessment. Yet this rapid advance of science and technology can be overshadowed by inconsistency in study design and sampling strategies; by the lack of quantitative or qualitative correlations of exposure, dose, or adverse effects; and by the lack of bioinformatics tools and analytical methods necessary to manage the volume of research findings. These limitations may render results uninterpretable and difficult, if not impossible, to use in risk assessment. Recommendations will be discussed to improve integrating systems biology and genomics into risk assessment so that the inherent promise of these new approaches can be realized.

Dose-responsive increase in sister-chromatid exchanges in bone-marrow cells of mice exposed nose-only to whole cigarette smoke

The effect of whole cigarette smoke exposure on bone-marrow sister-chromatid exchanges (SCEs) was studied in B6C3F1 mice. Animals were exposed nose-only to 10% (v/v) cigarette smoke 5 days/week for 2 weeks. Four dose levels of cigarette smoke (1, 4, 9 and 18 exposures/day) were studied using 2 cigarette types, Kentucky reference 3A1 (3A1) and American Blend (AB). A single exposure represented approximately 1 cigarette. A dose-dependent increase in SCEs was observed for both the 3A1 and AB cigarettes at dose levels which had no effect on bone-marrow cell-replication kinetics. These findings represent the first demonstration of a dose-responsive increase in cigarette smoke-induced SCEs in a rodent model system.

Scientific and Legal Perspectives on Science Generated for Regulatory Activities

This article originated from a conference that asked “Should scientific work conducted for purposes of advocacy before regulatory agencies or courts be judged by the same standards as science conducted for other purposes?” In the article, which focuses on the regulatory advocacy context, we argue that it can be and should be. First, we describe a set of standards and practices currently being used to judge the quality of scientific research and testing and explain how these standards and practices assist in judging the quality of research and testing regardless of why the work was conducted. These standards and practices include the federal Information Quality Act, federal Good Laboratory Practice standards, peer review, disclosure of funding sources, and transparency in research policies. The more that scientific information meets these standards and practices, the more likely it is to be of high quality, reliable, reproducible, and credible. We then explore legal issues that may be implicated in any effort to create special rules for science conducted specifically for a regulatory proceeding. Federal administrative law does not provide a basis for treating information in a given proceeding differently depending on its source or the reason for which it was generated. To the contrary, this law positively assures that interested persons have the right to offer their technical expertise toward the solution of regulatory problems. Any proposal to subject scientific information generated for the purpose of a regulatory proceeding to more demanding standards than other scientific information considered in that proceeding would clash with this law and would face significant administrative complexities. In a closely related example, the U.S. Environmental Protection Agency considered but abandoned a program to implement standards aimed at “external” information.

Industry-Government Collaboration

Dan Ferbers article “NIEHs toxicologist receives a ‘gag order’” (News of the Week, 9 August, p. [915][1]) refers to a

Symposium: Current Issues in Risk Assessment, January 1988–January 1989: Sponsored by International Life Sciences Institute, Risk Science Institute, Society of Risk Analysis, and Brookings Institution

4-million research collaboration between the National Institute of Enviromental Health Sciences (NIEHS) and the chemical industry, but does not explain the rigorous

Applying new biotechnologies to the study of occupational cancer--a workshop summary.

In September 1986, the Risk Science Institute, Society of Risk Analysis. and Brookings Institution established a monthly seminar series in risk analysis and management in Washington. D.C. The presentations were very well received and numerous requests were received for transcripts or manuscripts. Several of the presentations were prepared for publication as a symposium in the Journal ofthe American College of Toxicology (vol. 4, 1988). The four papers from the present symposium represent the second compilation of the seminar series. Risk analysis and management are dynamic and rapidly evolving fields. Dramatic shifts occur in the concerns of the public health and environmental communities, as well as in the public’s understanding and perception of the relative importance of various types of threats to its health and safety. Insights and developments conceining fundamental mechanisms and procedures continue to reshape our ability to estimate the risks in our society. This Symposium on Current Issues in Risk Assessment addresses areas of topical interest and reflects some of the current controversies in the field. Margaret Kripke discussed the implications of increased ultraviolet (UV) radiation due to stratospheric ozone depletion in terms of increased incidence of various types of skin cancers and ocular cataracts. It is notable that there is growing evidence that UV radiation can cause immunologic changes in humans as well as in anima1,s. In the arena of carcinogen risk assessment, Rosenkranz and Klopman studied the structural features of 7, 12-dimethyl anthracene (DMBA) using a computerized structure evaluation method. The authors suggested1 that this approach can be used to gain mechanistic insights into carcinogens and mutagens. Cohen and Ellwein have developed a biological model of carcinogenesis that can be expressed mathematically and have identified the carcinogenic process as directly altering the genome (genotoxic) or increasing the proliferative rate of the tissues. The model has been validated biologically utilizing bladder tumor incidence data in rats. Ernest E. McConnell discussed the concept of maximum tolerated dose (MTD), how it became an integral part of chronic toxicity and carcinogenesis studies, as well as the debate it has engendered, and he outlined the principal advantages and disadvantages of its use. In the final presentation, James Trosko challenged the paradigm of “carcinogenesis as mutagenesis” that guides basic research on mechanism(s) of carcinogenesis, the design of bioassay test protocols, and the problem of risk assessment after exposure to “carcinogenic” chemicals. Trosko suggested that short-term mutagenicity tests are inadequate because they do not assess factors influencing cell homeostasis (i.e., intercellular communication) and cell growth (i.e.. mitogenesis) and cannot provide the kind of scientific information needed to make important regulatory decisions. These articles demonstrate the multidisciplinary approach that must he taken in risk analysis and the active investigations underway to improve the science and aid in making decisions about risks in our society.