Threshold Dose Response Research Articles

Threshold dose–response association between smoking pack-years and the risk of gallbladder cancer: A nationwide cohort study

Background and aimsThe association between smoking and gallbladder cancer (GBC) risk is unclear. We investigated the association between smoking (including pack-years) and GBC risk. We also examined the combined effects of smoking and diabetes or prediabetes on GBC risk. MethodsThis Korean nationwide cohort study included 9,520,629 adults without cancer who underwent national health screening in 2009 and were followed-up until 2018. Multivariable Cox proportional hazards models were used to determine risk estimates after adjusting for potential confounders. ResultsDuring 78.4 million person-years (mean 8.2 ± 0.9 years) of follow-up, we identified 6066 patients with newly diagnosed GBC. Current and former smokers were associated with increased GBC risk (hazard ratio [HR], 95% confidence interval [CI]: 1.117, 1.029–1.212 and 1.105, 1.016–1.202, respectively). Smoking of 20 to <30 and ≥30 pack-years was independently associated with increased GBC risk compared with never smoking (HR, 95% CI; 1.241, 1.100–1.400 and 1.231, 1.107–1.370, respectively). However, smoking of <10 and 10 to <20 pack-years was not. This threshold dose–response association between smoking pack-years and GBC risk was observed regardless of the glycaemic status (all P < 0.01). Furthermore, smoking of ≥20 pack-years and hyperglycaemia had a synergistic effect on the GBC risk (all P < 0.01). Smokers with ≥20 pack-years with diabetes had the highest risk of GBC compared to never smokers with normoglycaemia (HR, 1.658; 95% CI, 1.437–1.914). ConclusionsSmoking was associated with increased GBC risk with a threshold dose–response effect for smoking pack-years. The risk of GBC increases synergistically when smoking and hyperglycaemia coexist. More individualised cancer prevention education is required to reduce GBC risk.

Evaluation of the mode of action and human relevance of liver tumors in male mice treated with epyrifenacil

Epyrifenacil (trademark name: Rapidicil®), a novel protoporphyrinogen oxidase (PPO)-inhibiting herbicide, induces hepatocellular adenomas and carcinomas in male CD-1 mice after 78 weeks treatment. The mode of action (MOA) of these mouse liver tumors and their relevance to humans was assessed based on the 2006 International Programme on Chemical Safety (IPCS) Human Relevance Framework. Epyrifenacil is not genotoxic and induced liver tumors via the postulated porphyria-mediated cytotoxicity MOA with the following key events: (#1) PPO inhibition; (#2) porphyrin accumulation; (#3) hepatocellular injury; with (#4) subsequent regenerative cell proliferation; and ultimately (#5) development of liver tumors. This article evaluates the weight of evidence for this MOA based on the modified Bradford Hill criteria. The MOA data were aligned with the dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity for a porphyria-mediated cytotoxicity MOA while excluding other alternative MOAs. Although the postulated MOA could qualitatively potentially occur in humans, we demonstrate that it is unlikely to occur in humans because of quantitative toxicodynamic and toxicokinetic differences between mice and humans. Therefore, this MOA is considered not relevant to humans, utilizing the IPCS Human Relevance Framework; consequently, a nonlinear, threshold dose response would be appropriate for human risk assessment.

Dose response and risk assessment: Evolutionary foundations

The present paper indicates that the origin of the LNT concept for ionizing radiation was based on insufficient understanding of evolution, which precluded the possibility of repair of gene mutation. The denial of such repair processes had important implications, leading to a belief in a linear dose response and thus in Hermann J Muller's proclamation of a Proportionality Rule for ionizing radiation. The paper documents how the lack of repair concept dominated the radiation geneticist community to the 1960s leading to the establishment of the linear no threshold dose response (LNT) model for radiation and chemical reproductive and cancer risk assessment. Research from the late 1950s onward would establish the occurrence, generality, and efficacy of genetic and cellular repair processes. While the assumption of a lack of gene mutation repair was wrong, Muller was correct that dose-response concepts need to be founded on mechanistic understandings of evolution. Such mechanisms require the integration of constitutive and inducible adaptive and repair mechanisms that operate in the low-dose zone. This perspective reflects the comment of Dobzhansky (1973) that “nothing makes sense in biology except in light of evolution.” While this is a powerful scientific dictum, it assumes a correct understanding of evolution, something that the origins of the LNT dose response lacked. Such modern mechanistic repair developments reveal that the historical foundations of LNT were flawed from the start. Nonetheless, they have been carried forward to the present time, principally by environmental health regulatory agencies that decoupled risk assessment policy from a sound evolutionary foundation.

Preliminary study on a new 3D radiochromic KI-Pluronic F-127 gel dosimeter for radiotherapy

This work concerns a new potassium iodide based radiochromic gel dosimeter with Pluronic F-127 gel matrix. The optimal dosimeter composition obtained in this work comprises 200 mM potassium iodide as a radiation sensitive colour changing compound, 200 mM fructose, 50 mM gluconic acid δ-lactone and 25% (w/w) poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic F-127) as a physical gel matrix. The potassium iodide changes from colourless to yellow colour upon ionizing radiation and the intensity of colour increases with an increase of radiation dose. The dosimeter after irradiation was measured using UV-Vis spectrophotometry to derive basic characteristics related to dose response: threshold dose, linear and dynamic dose response, dose sensitivity as well as stability over time after irradiation. Water equivalence was also analysed with respect to other similar 3D radiochromic gel dosimeters for a broad photon energy range. The results obtained indicate that the KI-Pluronic F-127 radiochromic gel dosimeter shows potential for use in 3D radiotherapy dosimetry.

Evidence of a Dose-Rate Threshold for Life Span Reduction of Dogs Exposed Lifelong to γ-Radiation.

Our return to a study on dogs exposed lifelong to cobalt-60 γ-radiation was prompted by a comment that data in dog studies have large statistical errors due to the small number of dogs. We located an earlier article on the same study that had a better mortality curve for the dogs in each dose-rate group. The median life span of the dogs in each group was tabulated, and the standard error of each was calculated. No statistically significant shortening of median life span was observed for the lowest dose-rate group at any reasonable significance level (P value: .005-.05), whereas for dogs with higher irradiation rates, life span shortening was statistically significant at highest reasonable significance level (P value: .005). The results were entered on a graph of life span versus dose rate, assuming a threshold dose–response model. The fitted line indicates that the dose-rate threshold for γ-radiation induced life span reduction is about 600 mGy per year, which is close to the value we found previously. Making allowance for the calculated standard errors, we conclude that this threshold is in the range from 300 to 1100 mGy per year. This evidence is relevant for emergency measures actions (evacuation of residents) and for nuclear waste management.

Linear-No-Threshold Default Assumptions are Unwarranted for Cytotoxic Endpoints Independently Triggered by Ultrasensitive Molecular Switches.

Crump's response in this issue to my critique of linear-no-threshold (LNT) default assumptions for noncancer and nongenotoxic cancer risks (Risk Analysis 2016; 36(3):589-604) is rebutted herein. Crump maintains that distinguishing between a low-dose linear dose response and a threshold dose response on the basis of dose-response data is impossible even for endpoints involving increased cytotoxicity. My rebuttal relies on descriptions and specific illustrations of two well-characterized ultrasensitive molecular switches that govern two key cytoprotective responses to cellular stress-heat shock response and antioxidant response element activation, respectively-each of which serve to suppress stress-induced apoptotic cell death unless overwhelmed. Because detailed dose-response data for each endpoint is shown to be J- or inverted-J-shaped with high confidence, and because independent pathways can explain background rates of apoptosis, LNT assumptions for this cytotoxic endpoint are unwarranted, at least in some cases and perhaps generally.

Radio-tolerance of finger millet Eleusine coracana (L.) Gaertn cultivars to ionizing radiation

In the current study, the basis of differential radio-tolerance to γ-irradiation of two cultivars of finger millet, Eleusine coracana (L.) Gaertn was established as assayed from their genotoxicity and oxidative stress responses. Seeds of E. coracana cultivars, cv. Bhairabi and cv. Suvra, were γ-irradiated at doses in the range 0–2.5 kGy. The mitotic index and frequency of chromosomal aberrations and micronuclei in root meristem cells of germinating seeds were determined. The formation of reactive oxygen species (ROS: H2O2, O2 •-, •OH), cell death, lipid peroxidation, activities of antioxidant enzymes: catalase, superoxide dismutase, guaiacol peroxidase, ascorbate peroxidase and glutathione reductase, levels of chlorophyll a and b, carotenoids, and total phenols, and the ROS-scavenging ability were determined in the leaves of six-day old seedlings. γ-Irradiation of seeds, in a dose-dependent fashion, significantly inhibited seedling growth and induced genotoxicity in the root meristem cells, and induced formation of ROS, cell death, lipid peroxidation, activation of antioxidant enzymes, and depleted photosynthetic pigments, phenols, and free radical scavengers in the leaf tissue. The threshold doses determined on the basis of lethal dose hundred (LD100) and dose fifty (D50) on the basis of seedling growth, the highest ineffective threshold dose (HITD) and the lowest effective threshold dose (LETD) on the basis of genotoxicity established higher radio-tolerance in cv. Bhairabi (LD100 = 2.0, D50 = 1.01, HITD =0.075, LETD =0.1 kGy) compared to cv. Suvra (LD100 = 1.0, D50 = 0.38, HITD =0.025, LETD =0.05 kGy). The genotoxicity assay validated the non-linear threshold (NLT) dose-response to γ-irradiation as opposed to the prevailing linear no-threshold (LNT) dose-response concept. The antioxidant response to γ-irradiation was correspondingly more pronounced in seedlings of the cv. Bhairavi than cv. Suvra. The differential radio-tolerance of the E. coracana cultivars appeared to be due to the differences in their antioxidative potentials.

Approaches for characterizing threshold dose-response relationships for DNA-damage pathways involved in carcinogenicity in vivo and micronuclei formation in vitro.

Assessing the shape of dose-response curves for DNA-damage in cellular systems and for the consequences of DNA damage in intact animals remains a controversial topic. This overview looks at aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of cellular DNA-damage/repair and their role in defining the shape of dose-response curves using an in vivo example with formaldehyde and in vitro examples for micronuclei (MN) formation with several test compounds. Formaldehyde is both strongly mutagenic and an endogenous metabolite in cells. With increasing inhaled concentrations, there were transitions in gene changes, from activation of selective stress pathway genes at low concentrations, to activation of pathways for cell-cycle control, p53-DNA damage, and stem cell niche pathways at higher exposures. These gene expression changes were more consistent with dose-dependent transitions in the PD responses to formaldehyde in epithelial cells in the intact rat rather than the low-dose linear extrapolation methods currently used for carcinogens. However, more complete PD explanations of non-linear dose response for creation of fixed damage in cells require detailed examination of cellular responses in vitro using measures of DNA damage and repair that are not easily accessible in the intact animal. In the second section of the article, we illustrate an approach from our laboratory that develops fit-for-purpose, in vitro assays and evaluates the PD of DNA damage and repair through studies using prototypical DNA-damaging agents. Examination of a broad range of responses in these cells showed that transcriptional upregulation of cell cycle control and DNA repair pathways only occurred at doses higher than those causing overt damage fixed damage-measured as MN formation. Lower levels of damage appear to be handled by post-translational repair process using pre-existing proteins. In depth evaluation of the PD properties of one such post-translational process (formation of DNA repair centers; DRCs) has indicated that the formation of DRCs and their ability to complete repair before replication are consistent with threshold behaviours for mutagenesis and, by extension, with chemical carcinogenesis.

Carcinogenicity and mode of action evaluation for alpha-hexachlorocyclohexane: Implications for human health risk assessment

Alpha-hexachlorocyclohexane (alpha-HCH) is one of eight structural isomers that have been used worldwide as insecticides. Although no longer produced or used agriculturally in the United States, exposure to HCH isomers is of continuing concern due to legacy usage and persistence in the environment. The U.S. Environmental Protection Agency (EPA) classifies alpha-HCH as a probable human carcinogen and provides a slope factor of 6.3 (mg/kg-day)−1 for the compound, based on hepatic nodules and hepatocellular carcinomas observed in male mice and derived using a default linear approach for modeling carcinogens. EPA's evaluation, last updated in 1993, does not consider more recently available guidance that allows for the incorporation of mode of action (MOA) for determining a compound's dose-response. Contrary to the linear approach assumed by EPA, the available data indicate that alpha-HCH exhibits carcinogenicity via an MOA that yields a nonlinear, threshold dose-response. In our analysis, we conducted an MOA evaluation and dose-response analysis for alpha-HCH–induced liver carcinogenesis. We concluded that alpha-HCH causes liver tumors in rats and mice through an MOA involving increased promotion of cell growth, or mitogenesis. Based on these findings, we developed a threshold, cancer-based, reference dose (RfD) for alpha-HCH.

Tremendous Human, Social, and Economic Losses Caused by Obstinate Application of the Failed Linear No-threshold Model

The linear no-threshold model (LNT) was recommended in 1956, with abandonment of the traditional threshold dose-response for genetic risk assessment. Adoption of LNT by the International Commission on Radiological Protection (ICRP) became the standard for radiation regulation worldwide. The ICRP recommends a dose limit of 1 mSv/year for the public, which is too low and which terrorizes innocent people. Indeed, LNT arose mainly from the lifespan survivor study (LSS) of atomic bomb survivors. The LSS, which asserts linear dose-response and no threshold, is challenged mainly on three points. 1) Radiation doses were underestimated by half because of disregard for major residual radiation, resulting in cancer risk overestimation. 2) The dose and dose-rate effectiveness factor (DDREF) of 2 is used, but the actual DDREF is estimated as 16, resulting in cancer risk overestimation by several times. 3) Adaptive response (hormesis) is observed in leukemia and solid cancer cases, consistently contradicting the linearity of LNT. Drastic reduction of cancer risk moves the dose-response curve close to the control line, allowing the setting of a threshold. Living organisms have been evolving for 3.8 billion years under radiation exposure, naturally acquiring various defense mechanisms such as DNA repair mechanisms, apoptosis, and immune response. The failure of LNT lies in the neglect of carcinogenesis and these biological mechanisms. Obstinate application of LNT continues to cause tremendous human, social, and economic losses. The 60-year-old LNT must be rejected to establish a new scientific knowledge-based system.

Radiation dose response estimation with emphasis on low dose range using restricted cubic splines: application to all solid cancer mortality data, 1950-2003, in atomic bomb survivors.

Using the all solid cancer mortality data set of the Life Span Study (LSS) cohort from 1950 to 2003 (LSS Report 14) data among atomic bomb survivors, excess relative risk (ERR) statistical analyses were performed using the second degree polynomial and the threshold and restricted cubic spline (RCS) dose response models. For the RCS models with 3 to 7 knots of equally spaced percentiles with margins in the dose range greater than 50 mGy, the dose response was assumed to be linear at less than 70 to 90 mGy. Due to the skewed dose distribution of atomic bomb survivors, the current knot system for the RCS analysis results in a detailed depiction of the dose response as less than approximately 0.5 Gy. The 6 knot RCS models for the all-solid cancer mortality dose response of the whole dose or less than 2 Gy were selected with the AIC model selection criterion and fit significantly better (p < 0.05) than the linear (L) model. The usual RCS includes the L-global model but not the quadratic (Q) nor linear-quadratic (LQ) global models. The authors extended the RCS to include L or LQ global models by putting L or LQ constraints on the cubic spline in the lower and upper tails, and the best RCS model selected with AIC criterion was the usual RCS with L-constraints in both the lower and upper tails. The selected RCS had a linear dose-response model in the lower dose range (i.e., < 0.2-0.3 Gy) and was compatible with the linear no-threshold (LNT) model in this dose range. The proposed method is also useful in describing the dose response of a specific cancer or non-cancer disease incidence/mortality.

An abuse of risk assessment: how regulatory agencies improperly adopted LNT for cancer risk assessment.

The Genetics Panel of the National Academy of Sciences' Committee on Biological Effects of Atomic Radiation (BEAR) recommended the adoption of the linear dose-response model in 1956, abandoning the threshold dose-response for genetic risk assessments. This recommendation was quickly generalized to include somatic cells for cancer risk assessment and later was instrumental in the adoption of linearity for carcinogen risk assessment by the Environmental Protection Agency. The Genetics Panel failed to provide any scientific assessment to support this recommendation and refused to do so when later challenged by other leading scientists. Thus, the linearity model used in cancer risk assessment was based on ideology rather than science and originated with the recommendation of the NAS BEAR Committee Genetics Panel. Historical documentation in support of these conclusions is provided in the transcripts of the Panel meetings and in previously unexamined correspondence among Panel members.

Diethylene glycol-induced toxicities show marked threshold dose response in rats

Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10g/kg DEG and blood, kidney and liver tissues were collected at 48h. Both rat strains treated with 10g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10g/kg DEG, but no DGA was present at 2 or 5g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments.

Oxidative stress and non-linear threshold (NLT) genotoxic dose responses to ionizing radiation in niger, Guizotia abyssinica (L.f.) Cass

Dose-responses of germination and seedling growth of plants namely Amaranthus blitum, Cajanus cajan, Eleusine coracana, Guizotia abyssinica, Lathyrus sativus and Lycopersicon esculentum obtained following γ-irradiation of seeds at a wide range of doses established G. abyssinica (LD50 = 0.32; D50 = 0.17 kGy) as highly radio-sensitive species. Seed-irradiation caused oxidative stress to the emerging seedlings that was evident by the dose-dependent increase in the generation of reactive oxygen species (ROS: H2O2, O2 •−, •OH), which in turn also showed good correlation with the dose-dependent induction of cell death, lipid peroxidation, protein oxidation, protein and non-protein thiols, and antioxidant enzymes activities, in the leaf tissue of G. abyssinica seedlings. The above biochemical endpoints could, therefore, serve as biomarkers of the previous exposure of seeds to ionizing radiation. Furthermore, the highest ineffective threshold (HITD = 0.019 kGy) and the lowest effective threshold (LETD = 0. 021 kGy) doses of ionizing radiation were determined on the basis of induction of cells with chromosome aberration (CA) or micronucleus (MN) in root meristems of the germinating irradiated seeds. The present G. abyssinica genotoxicity assay thus validated the non-linear threshold (NLT) dose-response to ionizing radiation as opposed to the prevailing linear no-threshold (LNT) dose-response concept.

Optimizing prediction of binge eating episodes: a comparison approach to test alternative conceptualizations of the affect regulation model.

BackgroundAlthough a wealth of studies have tested the link between negative mood states and likelihood of a subsequent binge eating episode, the assumption that this relationship follows a typical linear dose–response pattern (i.e., that risk of a binge episode increases in proportion to level of negative mood) has not been challenged. The present study demonstrates the applicability of an alternative, non-linear conceptualization of this relationship, in which the strength of association between negative mood and probability of a binge episode increases above a threshold value for the mood variable relative to the slope below this threshold value (threshold dose response model).MethodsA sample of 93 women aged 18 to 40 completed an online survey at random intervals seven times per day for a period of one week. Participants self-reported their current mood state and whether they had recently engaged in an eating episode symptomatic of a binge.ResultsAs hypothesized, the threshold approach was a better predictor than the linear dose–response modeling of likelihood of a binge episode. The superiority of the threshold approach was found even at low levels of negative mood (3 out of 10, with higher scores reflecting more negative mood). Additionally, severity of negative mood beyond this threshold value appears to be useful for predicting time to onset of a binge episode.ConclusionsPresent findings suggest that simple dose–response formulations for the association between negative mood and onset of binge episodes miss vital aspects of this relationship. Most notably, the impact of mood on binge eating appears to depend on whether a threshold value of negative mood has been breached, and elevation in mood beyond this point may be useful for clinicians and researchers to identify time to onset.

The nickel dose–response relationship by filaggrin genotype (FLG)

On skin contact, nickel accumulates in the stratum corneum, where it is probably bound to proteins and amino acids. One probable contributor is filaggrin, which binds nickel avidly. Filaggrin gene (FLG) null mutations lead to a complete lack of filaggrin production from the affected allele, and have been associated with an increased risk of nickel contact sensitization in German and Danish adults. To investigate whether the experimental nickel elicitation threshold level differed between heterozygous FLG mutation and non-mutation carriers. Thirteen nickel-sensitized female patients, seven heterozygous mutation carriers and six non-mutation carriers (genotyped for R501X, 2282del4, or R2447X), were patch tested and performed a repeated open application test (ROAT) with a nickel sulfate dilution series. Logistic threshold dose-response analyses were used to test for differences between the two groups. No difference was found in the dose-response relationship between FLG mutation and non-mutation carriers. On the basis of this small patient study, it appears that the elicitation threshold level for nickel is independent of FLG null mutation single-allele carrier status.

Mode of action for inorganic arsenic toxicity and carcinogenesis

Inorganic arsenic (iAs) at high doses is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. It is also associated with non-cancer toxicities. An understanding of the mode of action (MOA) for arsenic-induced effects is needed to develop a scientifically-based risk assessment. To determine an MOA for iAs induced toxicities, it is necessary to understand the metabolism, kinetics, cell transport, and interaction with specific proteins of iAs. Based on in vitro investigations using animal and human cells, studies from animal models, and clinical and epidemiological studies, we have proposed an MOA involving formation of sufficient levels of reactive trivalent metabolites which interact with critical free sulfhydryl groups, leading to cytotoxicity and regenerative cell proliferation. There is a strong correlation between in vitro cytotoxicity (>0.1 μmol/L trivalent arsenicals) and the no effect levels in rodents [approximately 1 ppm (1 ppm = 1 mg/L) of water or diet]. In epithelial target tissues, the cytotoxic effects of iAs result in chronic precursor lesions which have the potential for an increased risk of developing cancer. In non-epithelial tissues, non-cancer toxicities such as hypertension and atherosclerosis develop. This MOA implies a non-linear, threshold dose–response relationship for both non-cancer and cancer end points of exposure to iAs.

Optimizing prediction of binge eating episodes: a comparison approach to test alternative conceptualizations of the affect regulation model

BackgroundAlthough a wealth of studies have tested the link between negative mood states and likelihood of a subsequent binge eating episode, the assumption that this relationship follows a typical linear dose–response pattern (i.e., that risk of a binge episode increases in proportion to level of negative mood) has not been challenged. The present study demonstrates the applicability of an alternative, non-linear conceptualization of this relationship, in which the strength of association between negative mood and probability of a binge episode increases above a threshold value for the mood variable relative to the slope below this threshold value (threshold dose response model).MethodsA sample of 93 women aged 18 to 40 completed an online survey at random intervals seven times per day for a period of one week. Participants self-reported their current mood state and whether they had recently engaged in an eating episode symptomatic of a binge.ResultsAs hypothesized, the threshold approach was a better predictor than the linear dose–response modeling of likelihood of a binge episode. The superiority of the threshold approach was found even at low levels of negative mood (3 out of 10, with higher scores reflecting more negative mood). Additionally, severity of negative mood beyond this threshold value appears to be useful for predicting time to onset of a binge episode.ConclusionsPresent findings suggest that simple dose–response formulations for the association between negative mood and onset of binge episodes miss vital aspects of this relationship. Most notably, the impact of mood on binge eating appears to depend on whether a threshold value of negative mood has been breached, and elevation in mood beyond this point may be useful for clinicians and researchers to identify time to onset.

EPA's Stage 2 Disinfection Byproducts Rules (DBPR) and Northern Kentucky Water: An Economic and Scientific Review.

Implementation of EPA's Stage 2 Disinfection Byproducts Rules (DBPR) in Northern Kentucky will cause a water rate increase of over 25%. Hence a review was undertaken, considering both economics and science in the context of President Obama's 2009 scientific integrity directive. The rules purport to avoid up to 0.49% of new bladder cancers by reducing the levels of DBPs in drinking water - a benefit so small that failure to implement will not cause unreasonable risk to health (URTH). It suggests at most one Northern Kentucky death avoided over 17 years for a cost of $136,000,000 ($1700 per household). Even this small benefit is probably overstated. EPA finds no "causal link" between DBPs and bladder cancer, and EPA acknowledges problems with the epidemiological data used in their calculation: the data appear contradictory and inconsistent, may be skewed toward "positive" results, and suggest different cancer sites than animal studies. Two similar international agencies disagree with EPA's conclusions. The science is based on the Linear No Threshold (LNT) dose response model for DBPs, but this may not be the correct model. 83% of EPA's epidemiological data show a statistical possibility that low levels of DBPs might be beneficial or have no effect.

Hormesis: Toxicological foundations and role in aging research

The field of toxicology adopted the threshold dose response in the early decades of the 20th century. The model was rapidly incorporated into governmental regulatory assessment procedures and became a central feature of chemical evaluation and assessment. The toxicological community never validated the capacity of this model to make accurate predictions throughout the remainder of the 20th century. A series of recent investigations have demonstrated that the threshold and linear dose response model failed to make accurate predictions in the low dose zone. Such findings demonstrate a profound failure by the toxicology community on the central pillar of its discipline and one with profound public health, medical and economic implications. Ironically, the hormetic dose response, which was rejected by the toxicology community during the early decades of the 20th century, accurately predicted responses in the low dose zone in the same three large-scale validation assessments. Within the past two decades hormetic dose responses have been frequently reported in the experimental biogerontology literature, associated with endpoints associated enhancing healthy aging and longevity. The low dose stimulatory response of the hormetic dose response model represents the quantification of enhanced biological performance in the experimental facilitation of aging quality via multiple endpoints and mechanisms and in the extension of lifespan in such animal models research.