• Toxic Testing: The Evidence
• Selected Bibliography
• Glossary of Testing Terms
• Toxic Notes

In 1938, the following nine guidelines were proposed for testing a new product, almost all involving either live animal models or simple chemical composition tests:

Table I: NECESSARY INFORMATION FOR DRUG TO BE FURNISHED BY PHARMACEUTICAL COMPANIES IN THEIR NDAS, AS PROPOSED BY GEILING AND CANNON IN 1938.

Chemical Composition Acute toxicity studies in two species Chronic toxicity studies with different doses in different species Observation of animals Pathological examination of animals Studies on the absorption and elimination of the chemical Study of interactions Knowledge of idiosyncrasies and untoward reactions

These early postulates prepared the way for almost all of the testing methodology currently accepted for establishing scientific evidence in toxic litigation cases. Since the Supreme Court's 1993 Daubert v. Merrell Dow decision it has become increasingly important for expert witnesses and attorneys to have a thorough understanding of recognized scientific principles and of the different testing methodologies used in order to have the evidence accepted by the court.

There are three basic types of testing methodologies currently accepted for accessing toxicity: in vivo (in life), using live animal models; in vitro (in glass), using tissue or cell cultures from human or animals; and epidemiology studies, charting the incidence and distribution of disease in the human population. Newer alternative methods are being developed such as constructing computer models and futuristic in vitro methods that rely on established data to generate results. However, these models have not been utilized long enough to satisfy regulatory agencies or the courts.

In reality, all of the testing methods listed are extremely complex and there are many variations to each of the procedures. All of the methods, however, have one thing in common: none of them can attest to having 100% validity. This dilemma results in the findings often being interpreted paradoxically. A striking example can be found in the same issue of a recent Carcinogenesis. One study is entitled "Mechanistic Data Indicate that 1,3 Butadine is a Human Carcinogen" while a second article indicates the opposite: "Epidemiological and Mechanistic Data Suggest that 1,3 Butadine Will Not be Carcinogenic to Humans at Exposure Likely to be Encountered in the Environment or Workplace".

Such a quandary is not an isolated incident in the scientific literature particularly in the complex area of risk assessment. It has been estimated that over 250,000 articles per month are added to the pool of scientific evidence, much of it contradictory. Being well armed with arguments, whether for or against the conclusions drawn from the scientific evidence presented, remains one of the best strategies for winning a toxic tort case.

Table II: TOXIC TESTING: ADVANTAGES & DISADVANTAGES

A D V A N T A G E S	In Vivo	In Vitro	Epidemiology	Alternative Methods
	1. Most drug approval cannot take place without in vivo testing	1. Allows quick testing of new products using human cells and is generally less expensive.	1. Large human populations can be studied over an extended period of time.	1. Models can be made from existing data that combine all types or combinations of the various toxicity tests.
	2. Most mammals share a common organ structure that permits extrapolation from one species to another.	2. Improves the capacity to test most pure chemicals or combinations of substances.	2. Usually admissible as evidence.	2. Computer simulations can solve the differential equations relating in vitro tests to in vivo results.
	3. Permits experimentation on live models in a controlled environment.	3. Most in vitro tests are relatively simple with easily quantifiable results.	3. Allows researchers to draw inferences between risk factors and disease.	3. Lowers the number of animals needed for testing.
	4. Longest established testing procedures with a greater abundance of studies.	4. Can reduce animal suffering.	4. The relative risk factor has been the basis of a large number of recent court rulings.	4. Can make more accurate assessments when data is sparse.
D I S A D V A N T A G E S	In Vivo	In Vitro	Epidemiology	Alternative Methods
	1. Time consuming and expensive.	1. May not fulfill the demands of being scientifically adequate for evidence.	1. There are fewer epidemiological studies.	1. None of the first generation alternative tests have met the validation criteria to serve as replacement tests for regulatory approval.
	2. Some scientists do not agree that animal studies can be used for human citing variation in organ structure or from one species to another.	2. Difficult to relate dosages that cause cellular toxicity to whole animal toxicity.	2. Undiscovered confounding factor or bias may be responsible for results.	2. May not be accepted as evidence.
	3. To override the "Time" factor unrealistic dose exposures may not be predictive for a target population exposed to lower doses.	3. Results are often highly variable and cannot be repeated.	3. Epidemiology cannot prove causation only association or high probability.	3. Computer modeling is in its infancy with many practical and theoretical challenges to be met.
	4. Animal studies are falling out of favor for ethical and scientific reasons.	4. The route of exposure, a variable that can have profound effects on test results, is often impossible to determine.	4. Human populations cannot be controlled which often relies on self reporting of evidence.	4. Models often have a built in bias from how the software is programmed.

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1. Goldberg, Alan M.; "Alternatives to Animals in Toxicity Testing", Sci Amer, 261(2):24-30, 1989.
2. Goldstein, Bernard D.; Henifen; "Reference Guide on Toxicology", Reference Manual on Scientific Evidence, Federal Judicial Center, 1994.
3. Hodel, C.; Bass; "Are Newer Scientific Concepts in Regulatory Toxicology Used Timely and Appropriately", Toxicology Letters, 64-65:149-155, 1992.
4. "Modeling in Biomedical Research: An Assessment of Current & Potential Approaches", ILAR News, 32(2):2-3, 1990.
5. Sun, Kai; et al; "Estimation of Acute Toxicity by Fitting a Dose-Time Response Surface", Risk Analysis, 15(2), 1995.
6. Thomas, D.; "Time Related Factors in Cancer Epidemiology", Crisp Data Base National Institute of Health, 1994.
7. Walum, E.; "Scientific Ethical and Legal Aspects of the Acceptance of In Vivo Methods in Regulatory Toxicology", Archives of Toxicology, Supp. 17, 1995. Wax, P.M.; "Elixers, Diluents & the Passage of the 1938 Federal Food, Drug and Cosmetic Act", Annals of International Medicine, 122(6):456-61, 1995.
8. Zbinden, G.; "Predictive Value of Animal Studies in Toxicology", Regul Toxicol Pharmacol, 14(2):167-77, 1991.

Complete Bibliography Available Upon Request

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ALTERNATIVE TESTING

Refers to those methods that replace, reduce, and refine existing whole-animal procedures.

BIOASSAY

A test for measuring the toxicity of an agent by exposing laboratory animals to the substance and observing the effects.

BIOLOGICAL MONITORING

Measurement of toxic agents or the results of their metabolism in biological materials, such as blood, urine, expired air, or biopsied tissue, to test for exposure to toxic agents or the detection of physiological changes due to exposure.

CONFOUNDING FACTORS

A variable that is related to both the exposure and the outcome. A confounding factor can obscure the relationship between the toxic agent and the adverse health outcome associated with that agent.

DOSE, DOSAGE

The measured amount of a chemical that is administered at one time, or that an organism is exposed to in a defined period of time.

DOSE-RESPONSE

The way a living organism responds to a toxic substance. The more time spent in contact with a toxic substance, or the higher the dose, the greater the organism's response. For example, a small dose of carbon monoxide will cause drowsiness; a large dose can be fatal.

DOSE-RESPONSE CURVE

A graphic representation of the relationship between the dose administered and the effect produced.

EPIDEMIOLOGY

The study of the occurrence and distribution of disease among people. Epidemiology is the study of groups of people to discover the cause of a disease, or where, when, and why a disease occurs.

EXTRAPOLATION

The process of estimating unknown values from known values.

GOOD LABORATORY PRACTICE (GLP)

A code developed by the federal government in consultation with the laboratory-testing industry that governs many aspects of laboratory standards.

IN VITRO

A research or testing methodology that employs an artificial or test tube system, or is otherwise outside of a living organism.

IN VIVO

A research or testing methodology that employs living organisms.

LETHAL DOSE 50 (LD50)

The dose at which 50% of laboratory animals die within a few days.

MAXIMUM TOLERATED DOSE (MTD)

The highest dose that an organism can be exposed to without causing death or significant overt toxicity.

NO OBSERVABLE EFFECT LEVEL (NOEL)

The level above which observable effects are believed to occur and below which no toxicity is observed.

NO THRESHOLD MODEL

A model for understanding disease causation which postulated that any exposure to a harmful chemical (such as a mutagen) may increase the risk of disease.

PHARMACOKINETICS

A mathematical model that expresses the movement of a toxic agent through the organ systems of the body to the target organ.

RISK ASSESSMENT

The use of scientific evidence to estimate the likelihood of adverse effects on the health of individuals or populations from exposure to hazardous materials and conditions.

SAFETY ASSESSMENT

Toxicological research that tests the toxic potential of a chemical in vivo or in vitro using standardized techniques required by governmental regulatory agencies.

STRUCTURE ACTIVITY RELATIONSHIPS (SAR)

A method used by toxicologists to predict the toxicity of new chemicals by comparing their molecular similarities and differences to compounds with known toxic effects.

THRESHOLD LIMIT VALUE (TLV)

A concentration of a substance to which most humans can be exposed without adverse effect.

Main Source: Reference Manual on Scientific Evidence

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What do undersized alligator penises, "lesbian" sea gulls, low sperm count and Bisphenol-A have in common? We're not sure; ask the National Academy of Sciences. They met recently for a two day conference in Washington, DC to debate whether common synthetic chemicals can reduce the ability to reproduce.

The Society of Toxicology (SOT) held their annual meeting in Anaheim, CA, March 10-14. A very hot topic proved to be "The Use and Misuse of Toxicology Evidence in the Courts". Members were familiarized with emerging legal standards for scientific evidence and given advice on serving as an expert witness.

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