Cross-species extrapolations and the biologic basis for safety factor determinations in developmental toxicology

Em, Johnson

doi:10.1016/0273-2300(88)90004-9

Cited by 31 publications

(10 citation statements)

References 45 publications

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“…39 Few people will argue that such testing is inappropriate or unnecessary for identifying potential carcinogens and developmental or reproductive toxicants, but these data must be carefully interpreted before the risk to humans exposed at low doses can be estimated. 27 ' 40 - 41 Some generalizations can be made about low-dose models. First, the various models will usually fit the rodent data in the dose region used in the animal tests.…”

Section: Dose-response Assessmentmentioning

confidence: 98%

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Potential Impact on Standards for Toxic Air Contaminants

Paustenbach¹,

Jernigan²,

Finley³

et al. 1990

Journal of the Air & Waste Management Association

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Since the Bhopal incident, the public has placed pressure on regulatory agencies to set community exposure limits for the dozens of chemicals that may be released by manufacturing facilities. More or less objective limits can be established for the vast majority of these chemicals through the use of risk assessment. However, each step of the risk assessment process (i.e., hazard identification, dose-response assessment, exposure assessment, and risk characterization) contains a number of pitfalls that scientists need to avoid to ensure that valid limits are established. For example, in the hazard identification step there has been little discrimination among animal carcinogens with respect to mechanism of action or the epidemiology experience. In the dose-response portion, rarely is the range of "plausible" estimated risks presented. Physiologically based pharmacokinetic (PB-PK) models should be used to understand the difference between the tissue doses and the administered dose, as well as the difference in target tissue concentrations of the toxicant between rodents and humans. Biologically-based models like the Moolgavkar-Knudson-Venzon (MKV) should be developed and used, when appropriate. The exposure assessment step can be significantly improved by using more sensitive and specific sampling and analytical methods, more accurate exposure parameters, and computer models that can account for complex environmental factors. Whenever possible, model predictions of exposure and uptake should be validated by biological monitoring of exposed persons (urine, blood, adipose) or by field measurements of plants, soil, fish, air, or water. In each portion of an assessment, the weight of evidence approach should be used to identify the most defensible value. In the risk characterization, the best estimate of the potential risk as well as the highest plausible risk should be presented. Future assessments would be much improved if quantitative uncertainty analyses were conducted. Procedures are currently available for making future assessments. By correcting some of these shortcomings in how health risk assessments have been conducted, scientists and risk managers should be better able to identify scientifically appropriate ambient air standards and emission limits.

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Section: Dose-response Assessmentmentioning

confidence: 98%

“…26 The same generalization applies to developmental and reproductive toxicants. 27 Clearly, the challenge is to determine to what degree exposure to such toxicants should be limited to ensure that the risk to humans is negligible.…”

Section: Hazard Identificationmentioning

confidence: 99%

Potential Impact on Standards for Toxic Air Contaminants

Paustenbach¹,

Jernigan²,

Finley³

et al. 1990

Journal of the Air & Waste Management Association

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“…59 As an example, MeistrichW has recently demonstrated that a factor of two is sufficient to account for interspecies differences in the effects of steroid hormones on sperm production in several mammalian species.…”

Section: Toxicologymentioning

confidence: 99%

Risk Assessment of Carcinogenic and Noncarcinogenic Chemicals

Johannsen

1990

Critical Reviews in Toxicology

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"Risk Assessment" is a general term used with increasing frequency by both scientists and regulators. Scientifically based risk assessments consider available toxicologic data when judging which agents pose a significant risk to the human population. The science of toxicology focuses on identifying potential hazards to human health using surrogate animal studies. Margins of Safety and establishment of ADIs (Acceptable Daily Intakes) are methods applied to animal test data to set "safe" levels of potential exposure. While the use of Safety Factors in development of the ADI can support a pragmatic conclusion of safety, this approach cannot provide estimates of the probability of harm or the degree of safety. Therefore, Quantitative Risk Assessment (QRA) methods using mathematical models have been advanced to extrapolate from animal exposures which are usually high to much lower human exposure levels where experimental response is absent. Such methodology has been applied primarily by U.S. regulatory agencies to experimental oncogenic responses to estimate the risks of chemical exposure. The present manuscript considers both methods for evaluation of chemical safety and focuses on the scientific merits and limitations of each.

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“…A common technique for extrapolating animal data to human exposure that is particularly applicable to reproduction is application of a safety factor to the animal data. A safety factor is a fraction of the NOEL of a relevant animal study that is considered safe for humans (Johnson, 1987a), and allows for response differences between humans and animals. An additional safety factor is often considered because the general population varies markedly from the most vulnerable to the least sensitive individual.…”

Section: Classes Of Adverse Effectsmentioning

confidence: 99%

“…Such &dquo;guilt by association&dquo; is notoriously unreliable for developmental toxicity (Tuchmann-Duplessis, 1980;Schumacher, 1975;Zimmerman, 1975) and tends to damage reputations and raise false alarms. In some instances, this mindset leads to reactionary or precipitous testing (Johnson, 1987a Appeals also extends protection to the offspring of workers, and thus developmental toxicity also becomes a basis for setting standards. Because OSHA has requirements for chemical evaluation and hazard determinations, the information becomes part of warning labels and material safety data sheets.…”

Section: Introductionmentioning

confidence: 97%

Perspectives On Reproductive and Developmental Toxicity

1986

Toxicol Ind Health

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Human reproduction and development is a cycle of interdependent events. Virtually all of its phases have been shown to be the primary target of one or more non-mutagenic exogenous agents. Such agents interfere with certain of the countless epigenetic or ontogenic events essential for normal completion of the cycle. Mutagens disrupt this cycle at some points, but the overwhelming majority of reproductive and developmental toxins are not mutagenic. As in all aspects of toxicology, the reproductive and developmental effects of chemicals are determined by the intrinsic nature of the chemical, the quantity of the chemical exposure, the duration of exposure and the stage of the cycle at which it occurs. Signs of reproductive toxicity range from reduced fertility to spontaneous abortion. Adverse effects on the conceptus are categorized as functional deficits, developmental retardation, structural abnormality and death. One or more of these is anticipated to occur as a result of excess exposure to most chemicals. Although the degree of hazard and risk potential can be calculated in each instance, chemicals differ markedly in their ability to interfere with reproduction (Amann, 1982) and/or development (Johnson, 1984). Standardized methods for reproductive and developmental toxicity safety evaluation are available for detecting adverse effects upon any aspect of reproduction and development. Data currently available establish that these state-of-the-art tests conducted in laboratory animals are often highly predictive of the type of adverse effect a particular chemical will have in humans, as well as the exposure level at which it will occur. By adding a modest safety factor to the no-observed-effect-level of well-executed animal studies, safe human exposure levels can be established. Responsibility for determining the intrinsic hazard potential and the risk estimate of exposure rests with manufacturers and major users of occupational and other environmental chemicals. As public awareness of reproductive and developmental hazards has increased in recent years, it has come to be understood that some chemicals have a predilection for causing reproductive impairment and/or disrupting development in the absence of other toxicity. Such substances must be identified to establish safe exposure levels and to determine the types of effects to be expected, should excessive human exposure occur. The setting of safe exposure levels is necessary both from the standpoints of ensuring public safety and avoiding product liability.

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Cross-species extrapolations and the biologic basis for safety factor determinations in developmental toxicology

Cited by 31 publications

References 45 publications

Potential Impact on Standards for Toxic Air Contaminants

Potential Impact on Standards for Toxic Air Contaminants

Risk Assessment of Carcinogenic and Noncarcinogenic Chemicals

Perspectives On Reproductive and Developmental Toxicity

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