Gradient

Regulatory Compliance

Methods & Policy

Overview
Example Projects
Experts

Overview

Gradient has extensive experience developing and evaluating the risk assessment methodology on which regulations are based. We are often invited to serve as experts on panels convened by US EPA's Science Advisory Board (SAB), the National Academy of Science (NAS), state agencies, and many others. We provide clients and regulators with credible, high quality scientific and technical analyses on a number of issues, such as the development of toxicity criteria, regulatory submissions, and calculation of risk-based remediation goals.

Example Publications:

Rhomberg, LR; Goodman, JE; Bailey, LA; Prueitt, RL; Beck, NB; Bevan, C; Honeycutt, M; Kaminski, NE; Paoli, G; Pottenger, LH; Scherer, RW; Wise, KC; Becker, RA. 2013. "A survey of frameworks for best practices in weight-of-evidence analyses." Crit. Rev. Toxicol. 43(9):753-784.

Rhomberg, LR; Lewandowski, TA. 2006. "Methods for identifying a default cross-species scaling factor." Human Ecol. Risk Assess. 12(6):1094-1127.

Bailey, LA; Goodman, JE; Beck, BD. 2009. "Proposal for a Revised Reference Concentration (RfC) for Manganese Based on Recent Epidemiological Studies." Reg. Tox. Pharmacol. 55:330-339.

Science, mathematics, physics  abstract

Example Projects

Development of Copper Remedial Action Criterion

Full Description

Gradient calculated a remedial action criterion (RAC) for copper in soil that is protective against the metal's gastrointestinal effects. Our analysis showed that the RAC value was most influenced by the concentration of copper in the stomach and the soil ingestion rate. Thus, we based the RAC on young children because of their higher soil ingestion rates.

Low-dose Extrapolation of Non-cancer Dose-response Curves

Full Description

Gradient reviewed a proposal by the National Academy of Sciences that linear low-dose extrapolation be used for non-cancer and cancer endpoints. We assessed the importance of several factors on the shape of non-cancer dose-response curves: additivity of low-dose effects to background disease processes; the impact of heterogeneity in sensitivity in the human target population; and dose-response relationships reported in epidemiology studies.

Pathophysiological Progression for Selected Endpoints

Full Description

Gradient assisted in the design of a model describing several frequently encountered toxicity endpoints in terms of a series of progressive pathophysiological steps. This dissection of the biological changes underlying toxicity aided the application of US EPA's mode-of-action guidance for judging relevance to humans and using precursor lesions and biomarkers in dose-response analysis.

US EPA Acute Dosimetry B

Full Description

Gradient examined how existing inhalation dosimetry approaches for chronic exposure need to be modified for use in assessing acute effects of short-term exposure. We constructed a generalized conceptual model that addresses the role of the pace of approach to pharmacokinetic steady state and the dependency of toxicity on the balance of target tissue damage and repair. The model provided a basis for animal-to-human extrapolations.

Scaling Toxicological Doses Across Species

Full Description

Gradient summarized the problems in cross-species extrapolation and identified data available to support the choice of a default scaling method. Our proposed approach relied on empirical data for acute lethality and pharmaceutical action, as well as general principals of allometry.

Development of a Manganese Reference Concentration

Full Description

Gradient reviewed recent occupational studies and used subclinical neurobehavioral effects data, predominantly on the motor system, to derive an updated reference concentration (RfC). We derived a comparable value using a manganese benchmark dose (BMD) modeling approach based on neurological effects as the point of departure.

Experts

Barbara D. Beck Read Bio

Catherine Petito Boyce Read Bio

Lorenz R. Rhomberg Read Bio

Peter A. Valberg Read Bio