Abstract
Although benchmark-dose methodology has existed for more than 20 years, benchmark doses (BMDs) still have not fully supplanted the no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) as points of departure from the experimental dose–response range for setting acceptable exposure levels of toxic substances. Among the issues involved in replacing the NOAEL (LOAEL) with a BMD are (1) which added risk level(s) above background risk should be targeted as benchmark responses (BMRs), (2) whether to apply the BMD methodology to both carcinogenic and noncarcinogenic toxic effects, and (3) how to model continuous health effects that aren’t observed in a natural risk-based context like dichotomous health effects. This paper addresses these issues and recommends specific BMDs to replace the NOAEL and LOAEL.
Similar content being viewed by others
References
Allen BC, Kavlock RJ, Kimmel CA, Faustman EM (1994a) Dose–response assessment for developmental toxicity II: comparison of generic benchmark dose estimates with no observed adverse effect levels. Fund Appl Toxicol 23: 487–495
Allen BC, Kavlock RJ, Kimmel CA, Faustman EM (1994b) Dose–response assessment for developmental toxicity III: statistical models. Fund Appl Toxicol 23: 496–509
Al-Saidy OM, Piegorsch WW, West RW, Nitcheva DK (2003) Confidence bands for low-dose risk estimation with quantal response data. Biometrics 59: 1056–1062
Bailer AJ, Noble RB, Wheeler MW (2005) Model uncertainty and risk estimation for experimental studies of quantal responses. Risk Anal 25: 291–299
Barnes DG, Daston GP, Evans JS, Jarabek AM, Kavlock RJ, Kimmel CA, Park C, Spitzer HL (1995) Benchmark dose workshop: criteria for use of a benchmark dose to estimate a reference dose. Regul Toxicol Pharm 21: 296–306
Catalano PC, Scharfstein DO, Ryan LM, Kimmel CA, Kimmel GL (1993) Statistical model for fetal death, fetal weight, and malformation in developmental toxicity studies. Teratology 47: 281–290
Crump KS (1984) A new method for determining allowable daily intakes. Fund Appl Toxicol 4: 854–871
Crump KS (1995) Calculation of benchmark doses for continuous data. Risk Anal 15: 79–89
Farland W, Dourson M (1992) Noncancer health endpoints: approaches to quantitative risk assessment. In: Cothern CR(eds) Comparative environmental risk assessment. Lewis Publishers, Boca Raton, pp 87–106
Faustman EM, Allen BC, Kavlock RJ, Kimmel CA (1994) Dose–response assessment for developmental toxicity I: characterization of database and determination of no observed adverse effect levels. Fund Appl Toxicol 23: 478–486
Filipsson AF, Sand S, Nilsson J, Victorin K (2003) The benchmark dose method—review of available models, and recommendations for application in health risk assessment. Cr Rev Toxicol 35: 505–542
Food Safety Council (1980) Proposed system for food safety assessment. Food Safety Council, Washington
Fowles JR, Alexeeff GV, Dodge D (1999) The use of benchmark dose methodology with acute inhalation lethality data. Regul Toxicol Pharm 29: 262–278
Gaylor DW (1983) The use of safety factors for controlling risk. J Toxicol Environ Health 11: 329–336
Gaylor DW (1992) Incidence of developmental defects at the no observed adverse effect level (NOAEL). Regul Toxicol Pharm 15: 151–160
Gaylor DW (1996) Quantalization of continuous data for benchmark dose estimation. Regul Toxicol Pharm 24: 246–250
Gaylor DW, Slikker W (1990) Risk assessment for neurotoxic effects. NeuroToxicology 11: 211–218
Gift J (2003) EPA’s Benchmark Dose Software (BMDS), Version 1.3.2. Available at: http://www.epa.gov/ncea/bmds.htm
Haber LT, Allen BC, Kimmel CA (1998) Non-cancer risk assessment for nickel compounds: issues associated with dose–response modeling of inhalation and oral exposures. Toxicol Sci 43: 213–229
Kang S-H, Kodell RL, Chen JJ (2000) Incorporating model uncertainties along with data uncertainties in microbial risk assessment. Regul Toxicol Pharm 32: 68–72
Kavlock RJ, Allen BC, Faustman EM, Kimmel CA (1995) Dose–response assessments for developmental toxicity IV: benchmark doses for fetal weight changes. Fund Appl Toxicol 26: 211–222
Kimmel CA, Gaylor DW (1988) Issues in qualitative and quantitative risk analysis for developmental toxicity. Risk Anal 8: 15–20
Kodell RL (2005) Managing uncertainty in health risk assessment. Int J Risk Assess Manage 5: 193–205
Kodell RL, Chen JJ, Gaylor DW (1995) Neurotoxicity modeling for risk assessment. Regul Toxicol Pharm 22: 24–29
Kodell RL, West RW (1993) Upper confidence limits on excess risk for quantitative responses. Risk Anal 13: 177–182
Krewski D, Van Ryzin J (1981) Dose response models for quantal response toxicity data. In: Csorgo M, Dawson DA, Rao JNK, Saleh AKMdE(eds) Statistics and related topic: Proceedings of the international symposium on statistics and related topics. North-Holland, Amsterdam, pp 201–231
Leisenring W, Ryan L (1992) Statistical properties of the NOAEL. Regul Toxicol Pharm 15: 161–171
Mohammed FK, St. Omer V (1986) Behavioral and developmental effects in rats following in utero exposure to 2,4-D/2,4,5-T mixture. Neurovbehav Toxicol Teratol 8: 551–560
NRC (National Research Council) (2000) Methods for developing spacecraft water exposure. National Academy Press, Washington, p 151
NRC (National Research Council) (2004) Spacecraft water exposure guidelines for selected contaminants, vol 1. National Academy Press, Washington, p 354
NTP (National Toxicology Program) (1987) Toxicology and carcinogenesis studies of 1,4-Dichlorobenzene (CAS No. 106-46-7) in F344/N rats and B6C3F1 mice (gavage studies). Technical Report No. 319. U.S. Department of Health and Human Services, Research Triangle Park
Razzaghi M, Kodell RL (2004) Quantitative risk assessment for developmental neurotoxic effects. Risk Anal 24: 1673–1681
Schlosser PM, Lilly PD, Conolly RB, Janszen DB, Kimbell JS (2003) Benchmark dose risk assessment for formaldehyde using airflow modeling and a single-compartment, DNA-protein cross-link dosimetry model to estimate human equivalent doses. Risk Anal 23: 473–487
Tukey J, Ciminera J, Heyse JB (1985) Testing the statistical certainty of a response to increasing dose of a drug. Biometrics 41: 295–301
West RW, Kodell RL (1999) A comparison of methods of benchmark dose estimation for continuous response data. Risk Anal 19: 453–459
West RW, Kodell RL (2005) Changepoint alternatives to the NOAEL. J Agric Biol Environ Stat 10: 197–211
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kodell, R.L. Replace the NOAEL and LOAEL with the BMDL01 and BMDL10 . Environ Ecol Stat 16, 3–12 (2009). https://doi.org/10.1007/s10651-007-0075-3
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10651-007-0075-3