National Toxicology Program: landmarks and the road ahead

National Toxicology Program: landmarks and the road aheadThe National Toxicology Program (NTP), a cross-agency unit of the Department of Health and Human Services (DHHS), is one of the focal points for government efforts aimed at generating, collecting, and coordinating data used for guiding public health decisions. Now 25 years old, the NTP is in the middle of a strategic planning effort to define how it will integrate new technologies with classical toxicological approaches to continue providing, according to the NTP's motto, "good science for good decisions."

In its current form, the NTP integrates activities from the NIEHS, the National Institute for Occupational Safety and Health (NIOSH), and the Food and Drug Administration (FDA) National Center for Toxicological Research (NCTR). Its mission is to evaluate agents of public health concern by developing and applying tools of modern toxicology and molecular biology, a mission it achieves through the use of several strategies. It designs studies on potential toxicants and works with outside groups and government labs to carry them out. It reviews and evaluates what's missing in understanding environmentally induced diseases. It then seeks to fill those gaps by collaborating and cooperating with federal agencies and with other domestic and foreign toxicology and public health organizations, and by carrying out research itself on human exposure and toxicity at laboratories housed at NIOSH and the NIEHS. It supports grants, contracts, and interagency agreements made through the NIEHS Division of Extramural Research and Training, and it supports the activities of three centers.

These activities have brought immense gains in knowledge for the scientific community. But there is more work still to do. Since the fall of 2003, the NTP has been engaged in developing and seeking public comment on a "roadmap" to guide the program's route forward over the next decade. The roadmap seeks to build on recent technological advances that will allow toxicology to evolve from a largely observational science to one that is more predictive, and thus in many ways more protective of public health.

The Journey Begins

The NTP's roots reach to the late 1960s, when concerns over the effects of environmental chemicals on human health began to grow among scientists, policy makers, public health officials, and the general public. Books like Silent Spring began to describe the relationship between humankind and the rest of the world as dangerously out of balance. The growth of the environmental movement in this decade led to greater public awareness of natural resources and the potentially harmful effects of environmental pollution. As law makers and the public became increasingly concerned about unforeseen effects of chemicals all around us--particularly those used in manufacturing, agriculture, and household products such as cleaners--new scientific and regulatory approaches were enacted to better understand these agents and decrease or eliminate human exposure to harmful agents.

Through the 1960s and 1970s, new agencies were formed and responsibilities within existing agencies were realigned in efforts to understand, classify, and/or regulate compounds of concern. The Toxicology Information Program at the National Library of Medicine began gathering toxicological information and compiling data banks to allow searching and comparison of the assembled material. The NIEHS, which was established in 1966 and became a full NIH institute in 1969, started a laboratory focused specifically on neurotoxicology in 1977, and in the same year hosted one of the first conferences on environmental estrogens. The Environmental Protection Agency (EPA) was founded in 1970 to pull environmental and health protection activities from across the government into one administrative unit. The FDA took on licensing authority for new biological therapeutic agents but transferred its responsibility for oversight of potentially hazardous materials and other dangers in home items (such as toys, furniture, clothing, and household chemical products) to the Consumer Product Safety Commission (CPSC), which was established in 1972.

In November 1978, Joseph Califano, secretary of the Department of Health, Education, and Welfare (the predecessor of today's DHHS), established the NTP as a cooperative and coordinating effort between agencies involved in public health. The program was seated at the NIEHS and placed under the leadership of then-NIEHS director David Rall. Kenneth Olden assumed directorship of both the NIEHS and the NTP in 1991. Despite this link, the NTP was and remains independent of the institute and of NIH.

The new program's charge included coordinating toxicological testing programs within public health agencies; strengthening the scientific basis of toxicology; developing and validating new assays and improved testing methods; and providing information about potentially toxic chemicals to health, regulatory, and research agencies across the government, to the scientific and medical communities, and to the general public.

Strengthening the Scientific Basis of Toxicology

Among its earliest activities, the NTP began collecting data from work going on across federal agencies; by 1980 it had generated a database comparing the results gained from a variety of widely used genotoxicity assays. By the end of that year, the program had issued its first Report on Carcinogens (ROC), a scientific and public health document identifying substances, mixtures, and circumstances of exposure that may lead to human cancers. The ROC has been updated periodically since then, and the eleventh edition is scheduled for release late in 2004.

In 1983, the NTP first developed and began using five standard categories to summarize the strengths of experimental data produced by its own laboratories and those of other agencies and industry in studies of chemical or physical agents. Four categories are based on a scale of confidence that ranges from "clear evidence" to "no evidence" of harm; a fifth judges that evidence amounts to an "inadequate study." The standardization helped make the program's long-term toxicity reports which can form the basis for policy recommendations on acceptable exposure levels and use of chemicals--more consistent across the range of agents and exposures studied. So, for example, when the State of California passed Proposition 65, the Safe Drinking Water and Toxic Enforcement Act of 1986, NTP data from the ROC were available to help the state set standards for discharge of potentially harmful agents into drinking water. By 1987, the NTP's standardized categorization had been used to classify conclusions from earlier federal studies of potential hazards, allowing the older information to be integrated into current data sets.

In a paper in the 22 May 1987 issue of Science, the NTP published the first comprehensive evaluation of genotoxicity assays, laying the groundwork for a more systematic approach to developing and validating new in vitro assays. At the same time, the program developed a battery of tests for assessing chemically induced immunotoxicity. As the 1980s drew to a close, the NTP began developing transgenic mouse models for toxicology and carcinogenicity testing, a new approach that would allow easier detection of end points such as tumors. (The NTP has continued to investigate the development of transgenic animals as research tools, and in 2003 launched a new technical report series to convey the findings from transgenic model systems.)

Revving Up in the 1990s

The 1990s saw the NTP embark on a series of new directions. One new effort, the Predictive-Toxicology Evaluation Project, was launched in 1990. Designed to use chemical structures for direct prediction of bioassay outcomes, the project published its first results in the October 1996 issue of EHP Supplements. Another new focus evolved in 1992, when the FDA and the NIEHS formed an interagency agreement to coordinate and jointly fund a phototoxicology research facility at the NCTR in Jefferson, Arkansas. Existing laboratory space at that facility was renovated in 1998 and 1999 to form a dedicated NTP Center for Phototoxicology. The center works to address the carcinogenic potential of chemicals when they are exposed to light or applied to photo-treated skin.