Physiologically Based Pharmacokinetic (PBPK) models apply a realistic mathematical description of physiology and biochemistry to simulate one or more exposures to trace elements or chemicals by one or more exposure routes, and simulate resulting absorption of such agents into the body, their systemic distribution and excretion, and (as applicable) their metabolic transformation into toxicologically active or inactive metabolites that are also systemically distributed and excreted. These models improve dose-response characterization by allowing experimental or environmental levels of exposure (or “applied dose”) to be re-expressed more meaningfully, as corresponding levels of biologically effective concentration(s) in target tissues(s) potentially affected by toxicity. After appropriate validation, PBPK models developed for animals or humans can be applied in either of two ways. A “forward” approach starts with a set exposure data, and uses PBPK modeling to estimate corresponding chemical concentrations in target tissue(s). A “reverse” approach starts with internal chemical-exposure measures (made on experimental or biomonitoring samples of blood, urine, or tissue), and uses PBPK modeling to estimate corresponding levels of exposure. Statistical and Monte-Carlo methods are used to estimate PBPK model parameters and to characterize uncertainty in PBPK model predictions.
Exponent offers product development, regulatory, and litigation support to clients that can benefit from PBPK-based analysis, assessment, critical evaluation, or scientific peer-review. Regulatory proceedings and litigation increasingly involve PBPK modeling methods to improve chemical exposure and risk assessments concerning occupational and environmental health, pharmaceuticals, food safety, and medical devices. Our scientists are experienced in developing and applying these methods to reconstruct exposure and dose, as well as to improve dose-response characterizations that play a critical role in risk assessment. Our PBPK modeling team applies PBPK techniques to complement and enhance Exponent’s exposure and risk assessments for-specific chemicals/agents, such as petroleum hydrocarbons, metals, pesticides, phthalates, organic solvents, and volatile/halogenated compounds. This expertise is also available to support pre-clinical pharmaceutical and medical-device evaluations, e.g., concerning expected rates of absorption, stability in tissues, hepatic clearance, and temporal plasma- and tissue-concentration profile, of test agents or materials, their metabolites, or any related contaminants.
Figure 1. Exponent PBPK modeling expertise was used to adapt biokinetic models for (a) soluble cobalt injected over a 20-day period into circulating human blood at age 20, and (b-d) for blood lead concentration (BPb) after human oral intake of lead. TWA = time-weighted average.