"The dose makes the poison," commonly attributed to Paracelsus1, is a cornerstone of our understanding of how our bodies respond to chemical, biological, and radiological agents found in food, consumer and industrial products, and the environment. Dose-response modeling in modern epidemiology and toxicology plays a key role to support scientifically sound public health and environmental policies.
Dose-response and exposure-response modeling provide a basis for the setting of regulatory limits, such as air quality, drinking water and food tolerance standards by providing approaches to extrapolation from observed data at high exposure levels to the exposures of regulatory interest.
Dose-response modeling has traditionally involved dividing a no-observed-adverse effect level (NOAEL) by appropriate uncertainty or safety factors or fitting observed dose-response data to simple mathematical forms using regression methods. The Benchmark Dose (BMD) approach formalizes the application the regression methods and evaluation of the results for deriving toxicity criteria. In contrast, biologically-based dose-response (BBDR) models combine the best available mechanistic knowledge to define mathematical functions used to fit dose-response data, allowing analysis of data sets with complex patterns of exposure to multiple carcinogens.
BBDR approaches include Physiologically Based Pharmacokinteic (PBPK) models that link administered to biologically effective target-tissue concentrations, mutation/clonal-proliferation models (such as the two-stage Moolgavkar-Venzon-Knudson or MVK model) that link tissue concentrations to tumor-occurrence likelihood, or a combination of these approaches referred to as a Physiologically Based Pharmacodynamic (PBPD) model. Because model selection can profoundly influence the dose-response predictions of the low-dose region, care must be taken to select appropriate modeling methods. Mode-of-action (MOA) understanding is especially important in developing dose-response models for carcinogens.
In the area of epidemiology, Exponent scientists have expertise in both traditional statistical techniques, such as logistic regression, and Cox proportional hazards regression, and BBDR models to support dose-response evaluation and modeling.
Exponent scientists have conducted a broad range of dose-response analyses and modeling to support important decisions. Our team includes nationally-recognized specialists key to developing the dose-response modeling methodology used today, and who thus are uniquely poised to provide highly effective technical support in the areas of:
- Regulatory limits
- Product registration
- Risk/Safety assessment
- Site-specific modeling
Examples of our work include:
- Analysis of a large epidemiological data set of Chinese tin miners exposed to three lung carcinogens, tobacco smoke, arsenic, and radon to estimate fraction of lung cancers attributable to each of these carcinogens in the cohort
- BBDR modeling for quantitative risk analyses of coke oven emissions and of refractory ceramic fibers
- Combined PPBK and MOA-specific MVK modeling to evaluate naphthalene cancer risk
- BMD analysis for acute contact dermatitis associated with chromium (VI)-containing compounds
- Dose-response modeling using EPA’s "R" modeling codes and BMDS to support risk assessments for pesticide registration
Bogen K. An adjustment factor for mode of action uncertainty with dual-mode carcinogens: The case of naphthalene-induced nasal tumors in rats. Risk Anal 2008, in press.
Bogen KT, Benson JM, Yost GS, Morris JB, Dahl AR, Clewell HJ, Krishnan K, Omiecinski CJ. Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action. Regul Toxicol Pharmacol 2008, in press.
Gujral J, Fowler J, Su S, Morgan D, Proctor D. Allergic contact dermatitis using two chemicals containing hexavalent chromium. The Toxicologist 2008; 102 (S-1):137.
Hazelton WD, Luebeck EG, Heidenreich WF, Moolgavkar SH. Analysis of a historical cohort of Chinese tin miners with arsenic, radon, cigarette, and pipe smoke exposures using the biologically-based two-stage clonal expansion model. Rad Res 2001; 156:7–94.
Moolgavkar SH, Brown RC, Turim J. Biopersistence, fiber length, and cancer risk assessment for inhaled fibers. Inhal Toxicol 2001; 13:755–772.
Moolgavkar SH, Luebeck EG, Turim J, Hanna L. Quantitative assessment of the risk of lung cancer associated with occupational exposure to refractory ceramic fibers. Risk Anal 1999; 19:599–611.
Moolgavkar SH, Luebeck EG, Anderson EL. Estimation of unit risk for coke oven emissions. Risk Anal 1998; 18:813–825.
Proctor D, Su S, Gujral J, Fowler J, Morgan D. Risk assessment of allergic contact dermatitis due to dermal exposures to hexavalent chromium. The Toxicologist 2008; 102(S-1):368.
1 The true origin of "the dose makes the poison" is unclear but Paracelsus (Swiss, 1493-1541) has written "Alle Ding sind Gift, und nichts ohn Gift; allein die Dosis macht, daß ein Ding kein Gift ist." ["All things are poison and nothing is without poison, only the dose permits something not to be poisonous."].