title: Linear low-dose extrapolation for noncancer heath effects is the exception, not the rule.
abstract: The nature of the exposure-response relationship has a profound influence on risk analyses. Several arguments have been proffered as to why all exposure-response relationships for both cancer and noncarcinogenic endpoints should be assumed to be linear at low doses. We focused on three arguments that have been put forth for noncarcinogens. First, the general "additivity-to-background" argument proposes that if an agent enhances an already existing disease-causing process, then even small exposures increase disease incidence in a linear manner. This only holds if it is related to a specific mode of action that has nonuniversal properties-properties that would not be expected for most noncancer effects. Second, the "heterogeneity in the population" argument states that variations in sensitivity among members of the target population tend to "flatten out and linearize" the exposure-response curve, but this actually only tends to broaden, not linearize, the dose-response relationship. Third, it has been argued that a review of epidemiological evidence shows linear or no-threshold effects at low exposures in humans, despite nonlinear exposure-response in the experimental dose range in animal testing for similar endpoints. It is more likely that this is attributable to exposure measurement error rather than a true nonthreshold association. Assuming that every chemical is toxic at high exposures and linear at low exposures does not comport to modern-day scientific knowledge of biology. There is no compelling evidence-based justification for a general low-exposure linearity; rather, case-specific mechanistic arguments are needed.
authors.affiliation: Gradient Corporation, 20 University Road, Cambridge, MA 02138, USA. lrhomberg@gradientcorp.com
authors.forename: Lorenz R
authors.initials: LR
authors.lastname: Rhomberg
authors.forename: Julie E
authors.initials: JE
authors.lastname: Goodman
authors.forename: Lynne T
authors.initials: LT
authors.lastname: Haber
authors.forename: Michael
authors.initials: M
authors.lastname: Dourson
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: James E
authors.initials: JE
authors.lastname: Klaunig
authors.forename: Bette
authors.initials: B
authors.lastname: Meek
authors.forename: Paul S
authors.initials: PS
authors.lastname: Price
authors.forename: Roger O
authors.initials: RO
authors.lastname: McClellan
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D002273:Carcinogens / Q000633:toxicity*; D004781:Environmental Exposure; D006706:Homeostasis; D006801:Humans; D015994:Incidence; D009369:Neoplasms / Q000139:chemically induced*; D017711:Nonlinear Dynamics; D018570:Risk Assessment; D020711:Threshold Limit Values
chemical_list: D002273:Carcinogens