Eula Bingham PhD John Zapp PhD deceased

4 Trends

4.1 Toxicological Testing

Concerns raised 20 years ago about the costs and validity of toxicological information that may be used for making risk assessments to protect workers and for business decisions on product development are still valid today.

When John Zapp wrote the first part of this chapter, it was the late 1970s and the other author, Eula Bingham, Assistant Secretary of Labor for Occupational Safety and Health, was grappling with the need for toxicological data on which to base occupational health and safety standards. It was during this period (1978) that the National Toxicology Program (NTP) began. This effort was intended to expand the carcinogen testing program of the National Cancer Institute that began during the 1960s.

Today, the National Toxicology Program (44) provides a significant portion of all new data on industrial chemicals used in the United State and in other countries. At present, 80,000 chemicals are used in the United States and an estimated 2,000 new ones are introduced annually to be used in products such as foods, personal care products, prescription drugs, household cleaners, and lawn care products. The effects of many of these chemicals on human health are unknown, yet people may be exposed to them during their manufacture, distribution, use, and disposal or as pollutants in our air, water, or soil.

The National Toxicology Program (NTP) was established by the Department of Health and Human Services (DHHS) in 1978 and charged with coordinating toxicological testing programs within the Public Health Service of the Department; strengthening the science base in toxicology; and providing information about potentially toxic chemicals to health regulatory and research agencies, scientific and medical communities, and the public (See Fig. 1.1). The NTP is an interagency program whose mission is to evaluate agents of public health concern by developing and applying the tools of modern toxicology and molecular biology. In carrying out its mission, the NTP has several goals:

• to provide toxicological evaluations of substances of public health concern;

• to develop and validate improved (sensitive, specific, rapid) testing methods;

• to develop approaches and generate data to strengthen the science base for risk assessment; and

• to communicate with all stakeholders, including government, industry, academia, the environmental community, and the public.

Nationally, the NTP rodent bioassay is recognized as the standard for identifying carcinogenic agents. However, the NTP has expanded its scope beyond cancer to include examining the impact of chemicals on noncancer toxicities such as those affecting reproduction and development, inhalation, and the immune, respiratory, and nervous systems. Recently a Center for Evaluation of Risks to Human Reproduction and a Center for the Evaluation of Alternative Toxicological Methods were created.

Policy overstte and chemical selection

Policy wersite and eremita I selection

Execute committee


Director A_

NTP Board of scientific counselors

Technical iepwts review subcommittee

Report on carcinogens subcommittee

Advisory committee on alternative toxico logical methods

Figure 1.1. National Toxicology Program. The National Toxicology Program (NTP) is headquartered at the NIEHS/NIH, and its director serves as director of the NTP. The Executive Committee composed of the heads of key research and regulatory Federal agencies provides oversight for policy issues. Science oversight and peer review are provided through a mix of Federal, academic, industrial, and public interest science experts.

NTP's testing program seeks to use mechanism-based toxicology studies to enhance the traditional approaches. Molecular biology tools are used to characterize interactions of chemicals with critical target genes. Examples of mechanism-based toxicology include identification of receptor-mediated toxicants, molecular screening strategies, use of transgenic animal models, and the development of alternative or complementary in vivo tests to use with rodent bioassays. Inclusion of such strategies can provide insight into the molecular and biological events associated with a chemical's toxic effect and provide mechanistic information that is useful in assessing human risk. Such information can also lead to the development of more specific and sensitive (and often less expensive) tests for use in risk assessment. There is a strong linkage between mechanism-based toxicology and the development of more biologically based risk assessment models. Such models are useful in clarifying dose-response relationships, making species comparisons, and identifying sources of interindividual variability.

Genetically altered or "transgenic" mouse models carry activated oncogenes or inactivated tumor suppressor genes involved in neoplastic processes in both humans and rodents. This trait may allow them to respond to carcinogens more quickly than conventional rodent strains. The advantage provided by such an approach compared with standard rodent models is that in addition to chemicals undergoing metabolism, distribution, and relevant pharmacokinetics, the neoplastic effects of agents can be observed in the transgenic models within a time frame in which few if any spontaneous tumors would arise.

During the past few years, the NIEHS/NTP has evaluated transgenic strains in toxicological testing strategies. The response for 38 chemicals was compared in two genetically altered mouse strains (p53def: p53+/- heterozygous and Tg.AC: n-Ha-ras transgene) with that of wild-type mice tested in chronic two-year bioassays. Findings from these studies were evaluated by the NTP Board of Scientific Counselors for their suitability in NTP toxicological evaluations. Based upon the NIEHS/NTP review, the transgenic models performed largely according to predictions; they identified all known human carcinogens and most of the multisite/multispecies rodent carcinogens but failed to identify completely rodent carcinogens that produced tumors in selected organs in two-year studies.

The use of these genetically altered mouse models holds promise in carcinogenesis research and testing and clearly is more rapid and less expensive than traditional NTP two-year bioassay studies. The challenge still facing the NTP is to design studies that address remaining questions and concerns and to explore how these models can be used in risk assessment.

The NIEHS Environmental Genome Project is a multicenter effort to identify systematically the alleles of 200 or more environmental disease susceptibility genes in the U.S. population. Information from this human exposure assessment initiative together with the environmental genome project will provide the science base essential for future, meaningful studies of gene/environment interactions in disease etiology.

As a part of an interagency human exposure assessment initiative, the NTP and the NCEH/CDC are collaborating on a pilot project to quantify approximately 70 chemicals in either human blood or urine that are considered endocrine disrupters. Biological samples from the National Health and Nutrition Examination Surveys (NHANES) are being tested. These data will be used to estimate human exposure to endocrine disrupting agents within the U.S. population and to identify those of greatest public health concern. This information can be used in prioritizing chemicals for study and in developing biologically based models for estimating human risks.

4.2 Human Genome

The revolution in genetics and specifically in mapping the human genome, as well as the development of transgenic animals, will radically change the way we evaluate chemical and physical agents. See chapter 7 by Dan Nebert in this volume.

The need to keep toxicologists apprised of the current thinking regarding many new advances in certain toxicological fields has led us to include a special chapter on genetics. Although human variability was recognized as a phenomenon during the last half of the nineteenth century, pharmacogenetics has now become a significant and critical element in understanding dose-response curves in every aspect of toxicology from predicting who can metabolize a chemical to a carcinogen to determining which patient may be at risk of death from a prescribed doses of an anticancer drug. This area will probably bring about the greatest changes in our understanding of worker responses to occupational exposures.

4.3 Global Workplaces

The workplaces of concern in early editions of Patty's were mainly those in U.S. factories where chemicals and certain processes occurred. Today, many of those activities and chemicals have moved overseas, and the scene is dynamic and changing as we write. Hopefully, the toxicological information contained in these volumes will be useful in global workplaces. We have welcomed authors from outside the United States, many of whom are outstanding toxicologists in their own countries and are known internationally. It is the hope of the editors that this trend will continue for Patty's in future editions. Without modern telecommunications and E-mail, we would not have the courage to propose such authors.

4.4 Mixtures

Mixtures have reemerged as a special concern in toxicology. Mainly during the period (1930-1970) when complex mixtures, particularly those derived from fossil fuels (petroleum fractions, coal tar) were being actively investigated, the issues revolved around finding the critical chemical in the complex mix that was responsible for its toxicology. Chemicals in these mixtures enhanced or inhibited the critical chemical. When chemical exposures occurred either together or in sequence as in chemical carcinogenesis, the concepts of initiation and promotion became part of understanding mixtures. Recognition that contributions from several chemicals affecting the same target organ could be at least additive and perhaps of concern in the workplace led the ACGIH to develop a methodology for simple mixtures.

As more information has been produced during the last 10 years regarding the content of hazardous waste sites, once again there are efforts to develop methodologies to account for multiple chemical exposures in attempting to assess risk. One of the most notable is the dioxins and the use of "equivalency factors." However, the way to determine any potential for interactions among a mixture of chemical exposures remains a problem in toxicology and will continue to require investigation in the future.

4.5 Training and Personnel

Current training programs in toxicology place heavy emphasis on genetics. Courses in genetics and molecular biology have largely replaced other fundamental medical disciplines such as biochemistry, physiology, and pharmacology. Sometimes, aspects of these elements are covered to a small extent in a toxicology course. Courses in risk assessment are usually elective. Most graduate programs in toxicology today provide little background for individuals seeking to work in industrial toxicology. On the other hand, the practical elements that remain as staples in industrial hygiene programs provide much that is useful in industrial toxicology. The deficiency in these programs is the lack of training in the biological sciences, since most industrial hygiene graduates have little or no toxicology unless they take it as an elective. The result is that industry today must be prepared to provide current graduates with on-the-job training equivalent to 2-3 years of a postdoctoral fellowship if they are to work in industrial toxicology.

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