Benchmarks in Toxicology
Society of Toxicology 50th Anniversary
To recognize the significance of the 50th anniversary of the Society of Toxicology (SOT), NIEHS, NTP, and SOT have created this website to highlight the "Benchmarks in Toxicology." From Paracelsus' declaration that "the dose makes the poison" to high throughput assays, many people, discoveries and events have shaped the modern field of toxicology. We hope this information will help to educate scientists and non-scientists alike to the formative benchmarks in the field.
Benchmarks in Toxicology
On Saturday, March 4, 1961, a small group met in Washington, DC, to lay the groundwork for a society devoted to the science of toxicology.
Fifty years later, the Society of Toxicology's fraternity of 7,000 practitioners will return to the nation's capital to commemorate the remarkable vision of its founding members.
As a tribute to this hallmark achievement, the Benchmarks in Toxicology was generated by the members to celebrate the discoveries of the past, the innovation of today's science, and the promise of new approaches and technologies that will continue to expand the field.
Here's to the next 50 years of advancement.
1500sParacelsus, a sixteenth century physician, demonstrated an understanding of the dose-response relationship by saying, "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy." Because of this, he is often referred to as the "father of toxicology."
1700The father of occupational medicine, Ramazzini raised concerns about workplace exposure to chemical hazards, including heavy metals. His book Diseases of Workers, first published in 1700, is the first comprehensive work on occupational diseases.
Sir Percivall Pott
1775In 1775 Pott, an English surgeon, became the first to describe an occupational cancer by linking scrotal cancer in chimney sweeps to soot exposure.
1960sDuring the late 1950s and early 1960s, in countries outside the United States, use of thalidomide to relieve morning sickness in pregnant women tragically resulted in thousands of babies born with limb deformities. Because of Kelsey's efforts at the U.S. Food and Drug Administration (FDA), the drug was never approved for use in the United States, thus averting a health disaster of greater proportion.
Irving Selikoff and J. Christopher Wagner
1960sSelikoff's groundbreaking studies of asbestos workers in the 1960s and Wagner's experimental approach to asbestos toxicology firmly established the connection between asbestos and lung disease. Their work provided the scientific basis for the regulation of asbestos.
1962In her 1962 book Silent Spring, Carson documented the detrimental effects of DDT (dichlorodiphenyltrichloroethane). She led the crusade against the use of the pesticide, which was eventually banned in 1972. Her work is credited with advancing the environmental movement and raising public awareness of environmental concerns.
Louis Casarett and John Doull
1975Casarett and Doull are the first editors of the textbook Toxicology: The Basic Science of Poisons (1975). Now in its seventh edition, the classic has been instrumental in training scientists for more than 35 years.
Pure Food and Drug Act
1906One of the first laws regulating the marketing of drugs was the 1906 Pure Food and Drug Act, which required accurate labeling of dosage and contents. Prior to this, many drugs touted unsubstantiated benefits from secret ingredients. Though the law has been largely replaced by the Federal Food, Drug, and Cosmetic Act, it did serve as the driving force for the eventual creation of the FDA.
Federal Food, Drug and Cosmetic (FD&C) Act
1938In 1937 more than 100 people died from sulfanilamide medicine mixed with deadly diethylene glycol. This disaster led to the passage of the FD&C Act, which required companies to perform safety testing and obtain FDA approval prior to marketing new drugs. The 1958 Food Additives Amendment, also called the Delaney Clause, prohibits the approval of any food additive shown to induce cancer in humans or animals.
Federal Insecticide, Fungicide and Rodenticide Act (FIFRA)
1947FIFRA provided for federal regulation of pesticide distribution, sale, and use to protect human health and prevent unreasonable adverse effects on the environment.
Federal agencies established
1960s - 70sIncreased public concern over the environment, health, and safety prompted the establishment of several key agencies. Today the U.S. government employs the largest number of toxicologists worldwide, at places such as the National Institute of Environmental Health Sciences (NIEHS), the U.S. Environmental Protection Agency (EPA), the Occupational Safety and Health Administration, and the National Institute for Occupational Safety and Health.
Lead reduction efforts
1970sThrough the Clean Air Act, the federal ban on lead-containing paint, and other efforts, the United States has seen a dramatic decline in average blood lead levels. Lead emissions in the United States have been reduced significantly since the 1970s.
Toxic Substances Control Act (TSCA)
1976Under TSCA, EPA regulates many existing chemicals and the introduction of new ones. TSCA addresses the production, importation, use, and disposal of specific chemicals, including polychlorinated biphenyls (PCBs), asbestos, and lead-based paint.
National Toxicology Program (NTP)
1978Recognizing that many human diseases were thought to be directly or indirectly related to chemical exposures, the NTP was established in 1978 to coordinate federal government toxicology testing; strengthen the science base in toxicology; develop and validate improved testing methods; and inform agencies, scientific and medical communities, and the public about potentially toxic chemicals.
Good laboratory practices (GLP)
1978GLP principles were established to promote the quality and validity of test data used for determining the safety of a variety of regulated products. For regulatory authorities, GLP promotes confidence that data from laboratory studies can be relied upon when conducting risk assessments.
Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA)
1980The crisis in New York's Love Canal neighborhood brought focus to the issue of toxic industrial waste. This and other high-profile hazardous substance cases prompted Congress to pass CERCLA, more commonly known as Superfund, to provide broad authority and funds to clean up hazardous waste sites.
Toxicology testing in the 21st century (Tox21)
2008Together, the NIEHS/NTP, EPA, FDA, and National Human Genome Research Institute are aiming to advance the state of toxicity testing using high throughput screening methods enabled by advances in computing, robotics, and cell-based analytical approaches. In addition to testing thousands of chemicals and mixtures, the collaboration seeks to identify new mechanisms of chemical activity in cells to better predict human response to toxic substances.
Methylmercury poisoning in Iraq
1971Seed grain coated with methlymercury fungicide was imported into Iraq and mistakenly consumed as food, killing hundreds. Studies of the tragedy provided toxicologists in regulatory agencies with one of the first opportunities to apply human data in establishing safe levels of exposure to a chemical.
Popularization of risk assessment
1970sA methodology for predicting the incidence of human cancers based on animal data offered quantitative estimates of risk for a given chemical dose. This model was quickly used to prioritize the regulation of dozens of substances found to be carcinogenic.
The Red Book
1983The National Research Council's Risk Assessment in the Federal Government: Managing the Process outlines principles for conducting risk assessments. This guide (and others) provides enduring concepts in toxicology-based approaches that continue to drive decision making in industry, academia, and government.
1980sThe mid-1980s brought a change in toxicologic thinking, from hazard and risk assessments based on typical endpoints in animal studies, toward a mechanism-driven integrated approach, including in vitro studies and modeling approaches.
1980sUsed in research and development and health risk assessment, physiologically based pharmacokinetic (PBPK) mathematical models describe the uptake, distribution, metabolism, and elimination of chemicals in the body, and are used to predict the toxicity of a chemical in humans based on animal data. In 1989, the EPA used PBPK data to revise its inhalation risk for the solvent methylene chloride.
Weight of Evidence
1980sBeginning with their assessment of color additives, officials at FDA validated use of the weight-of-evidence approach to evaluate the findings of a body of studies versus a positive, statistically significant result from a single study.
Health risk assessment of lead
1986EPA established a certain blood lead level as a level of concern for adverse health effects to children's neurobehavioral development. This assessment was at the forefront of major changes in public health policies, including removal of lead from gasoline.
Threshold of toxicological concern (TTC)
1990sTTC is a human exposure threshold value set for chemicals below which there would be no appreciable risk to human health. TTC has become a valuable risk assessment tool for substances present in products in very low amounts, even where toxicity data may be lacking.
Bovine corneal opacity and permeability (BCOP) assay
2008In an effort to minimize harm to animals used in research, members of the federal Interagency Coordinating Committee on the Validation of Alternative Methods recommended approval for use of the BCOP assay, an in vitro test for detecting eye irritants.
Discovery of cytochrome P450 enzymes (CYPs)
1955The discovery of CYPs helped to understand how chemicals are transformed in the body into active compounds. CYPs in humans are present throughout the body and play an important role in drug metabolism, bioactivation, and excretion.
1960sKey insights into the physical and chemical properties of small particles in gases helped reveal how adverse health effects occur in humans. These contributions in inhalation toxicology continue to have a great impact on our understanding of air pollutants.
1960sNumerous studies, including research focusing on worker exposure, expanded our understanding of the toxicity and metabolism of industrial solvents.
Role of electrophilic intermediates
1971Electrophilic intermediates were identified as key contributors in the conversion of chemicals into active agents. This opened the door to understanding the metabolic activation of toxicants, carcinogens, and pharmaceuticals.
1970sResearch on formaldehyde, a chemical used in a variety of materials from consumer products to disinfectants, revealed complicated mechanisms for toxicity.
1970sThis simple screening assay examines bacterial mutation to determine whether a chemical damages DNA and might cause cancer, and today is still one of the most utilized tests to screen chemicals and drugs before approval is received for marketing. The Ames test has broad application in pharmaceutical, pesticide, industrial chemical, and environmental sample testing, and it has reduced animal use in testing.
Aryl hydrocarbon receptor (AhR)
1976The cellular environmental sensor AhR is mediates the expression of genes involved in the metabolism and detoxification of environmental pollutants such as dioxins and polychlorinated biphenyls. This discovery was critical to the understanding of toxicology at the molecular level.
Alpha 2u globulin nephropathy
1980sThis male rat-specific disease of the kidney increases the incidence of renal cancer. Research has demonstrated that the biochemical processes for the disease in male rats cannot occur in humans. This finding has implications for risk assessment, which generally assumes that chemicals producing tumors in animals are potentially hazardous to humans.
1980sPioneering research illustrates the ability of carcinogens to act through genotoxic (altering genetic material of cells) and non-genotoxic mechanisms. This led to the discovery of several mechanisms that cause DNA damage or increased cell proliferation.
1990sToxicogenomics (a field combining toxicology with genomics research) and other omics technologies, together with groundbreaking advances in analytical and computational capability, improve our understanding of the pathways leading to toxicologic effects.