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Hazard Characterization and Dose–Response Assessment
Published in Ted W. Simon, Environmental Risk Assessment, 2019
These adjustments reflect the application of Haber’s Rule, developed early in the 20th century to address issues of the toxicity of poison gas used as a weapon of war. At that time, scientists observed that both concentration and time interacted to produce toxicity, and Haber’s Rule indicates that concentration and exposure time are both factors in producing an effect—briefly, c × t = k, where k is proportional to the effect. In essence, k represents the AUC for exposure. Hence, an inhalation exposure to 10 ppm for one hour will be equivalent to an exposure to 1 ppm for ten hours. Haber’s Rule has been shown to be applicable for both the inhalation and oral routes of exposure.315
Inhalation Toxicology of Chemical Agents
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Stanley W. Hulet, Paul A. Dabisch, Robert L. Kristovich, Douglas R. Sommerville, Robert J. Mioduszewski
It is widely known that the toxicity caused by inhalation of vapor of a harmful agent is dependent on dosage, which, in turn, is a product of the concentration of the substance in the air (C) and the duration of the exposure (T), or CT. As early as 1924, Haber developed a formula for assessing the toxic effects of harmful vapors. Haber’s rule is described by the equation (Derelanko, 2002)
Use of Biomarkers in Occupational Safety and Health
Published in Anthony P. DeCaprio, Toxicologic Biomarkers, 2006
Under Haber’s Rule, dose is considered to be a function of contaminant concentration and exposure time. In an occupational setting, however, exposure is impacted by many variables such as body size, personal hygiene, work practice, level of fitness, smoking, alcohol and drug usage, and nutritional status. Dose is further impacted by inter- and intraindividual variability in pharmacokinetics and pharmacodynamics. Biological monitoring has an advantage in that it can take into account all of these variables while providing a more accurate estimate of internal dose, thus serving as a useful adjunct to workplace air monitoring.
Risk characterisation of constituents present in jamu to promote its safe use
Published in Critical Reviews in Toxicology, 2021
Suparmi Suparmi, Dasep Wahidin, Ivonne M. C. M. Rietjens
When evaluating the risks of genotoxic carcinogenic constituents detected in jamu by the MOE approach it is also of importance to note that risk assessment by the MOE approach is based on the assumption of daily exposure during a whole lifetimes. To correct exposure estimates for use during shorter periods of time, such as for example only during periods of illness, it has been proposed to use Haber’s rule as a first tier approach to correct for shorter than lifetime exposure (Doull and Rozman 2000; Felter et al. 2011). Haber’s rule states that the dose times the exposure duration is constant k is the toxic outcome, C is the concentration (or dose) of the toxic chemical, and T is the duration of exposure. The numbers 1 and 2 indicate two different exposure regimens, for example, lifetime exposure to a dose C1 and 2 weeks yearly during a whole lifetime exposure to a dose C2, respectively). This implies that one could correct for shorter time of exposure in a linear way. Using Haber’s rule, EDIs and resulting MOEs for shorter than daily lifetime exposure were obtained.
Development of an acute, short-term exposure model for phosgene
Published in Toxicology Mechanisms and Methods, 2019
Stephen T. Hobson, Robert P. Casillas, Richard A. Richieri, Robert N. Nishimura, Richard H. Weisbart, Rick Tuttle, Glenn T. Reynolds, Missag H. Parseghian
Phosgene (carbonyl chloride), a toxic colorless gas at room temperature, is used widely in industry in the synthesis of plastics, dyes, pharmaceuticals, and agro-chemicals. Its ready availability and high toxicity make it an agent of concern to the military and to homeland security authorities (Bast and Glass-Mattie 2015; Baggett and Simpkins 2018). Indeed, during World War I, the greatest number of fatalities was caused by phosgene (Summerhill et al. 2017). Developed as a war gas by Fritz Haber, his postwar studies on acute lethality led him to suggest a relationship, now known as Haber’s rule, where the physiological effects of phosgene and other toxic gasses are proportional to the concentration and duration of exposure (C × t) (Haber 1924). As an aside, this was not a new toxicological observation, having been first proposed by Warren (1900) in studies on the toxicity of salt solutions that kill the microscopic planktonic crustacean, Daphnia magna.
Phosgene: toxicology, animal models, and medical countermeasures
Published in Toxicology Mechanisms and Methods, 2021
Stephen T. Hobson, Richard A. Richieri, Missag H. Parseghian
Historically, Haber’s Rule has been a guiding hypothesis when interpreting toxicity results in an animal model (Miller et al. 2000). Mathematically predicting the physiological effects of a toxin on an organism in proportion to the toxin’s concentration and the organism’s duration of exposure was first proposed by Warren (Warren 1900) regarding the toxicity of salt solutions that kill the planktonic crustacean, Daphnia magna. However, it is Fritz Haber whose name graces the iconic formula C × t, based on work he did exposing cats to phosgene (Haber 1924). Ironically, Haber was not an adherent to the idea that C × t applied linearly to all intoxications; he appreciated the importance of the time factor, particularly for chronic exposures, where metabolism and detoxification (toxicodynamics and toxicokinetics) would begin to influence the toxic load (Rozman and Doull 2000). To improve the accuracy of the dose response equation, ten Berge et al. (ten Berge et al. 1986) introduced the ‘toxic load exponent’ (ne) for the concentration parameter (Figure 3). An exponent for the time parameter (p) improves toxic load modeling further, particularly for chronic studies; however, if p < 1 the toxicity relies more on concentration than exposure duration, and conversely if p > 1 the toxic effect may not be linear over an extended period of time. In a survey of 21 inhaled toxicants, 14 had an estimated p < 0.45 and only 3 had p > 1 (Belkebir et al. 2011). Those with a p > 1 did not exceed p = 1.25. While the survey did not cover phosgene, the results suggest our primary focus here on the concentration parameter with Toxic Load = p is presented in (Miller et al. 2000).