J-shaped Dose-response Curves Research Articles

Molecular Pathway Changes Associated with Different Post-Conditioning Exercise Interventions After Experimental TBI.

Traumatic brain injury (TBI) causes complex, time-dependent molecular and cellular responses, which include adaptive changes that promote repair and recovery, as well as maladaptive processes such as chronic inflammation that contribute to chronic neurodegeneration and neurological dysfunction. Hormesis is a well-established biological phenomenon in which exposure to low-dose toxins or stressors results in protective responses to subsequent higher-level stressors or insults. Hormetic stimuli show a characteristic U-shaped or inverted J-shaped dose-response curve, as well as being time and exposure-frequency dependent, similar to pre-conditioning and post-conditioning actions. Voluntary exercise interventions, before or after injury, appear to follow these general hormetic principles. But the molecular alterations associated with exercise interventions or more general hormetic responses have received only limited attention. In this study, we used a well-characterized mouse TBI model to assess the effects of different post-conditioning exercise-intervention paradigms on diverse molecular pathways, including neuroinflammation regulators, and post-traumatic neurological deficits. We generated high-throughput gene expression data and associated molecular pathway analyses to assess the potential molecular mechanisms associated with time- and duration-dependent voluntary exercise intervention, as well as time after treatment. Importantly, we also used newer analytical methods to more broadly assess the impact of exercise on diverse molecular pathways. TBI caused long-term changes in multiple neuroinflammation markers and chronic cognitive dysfunction. Notably, all delayed, post-conditioning exercise interventions reduced post-traumatic neuroinflammation and/or attenuated the related cognitive changes, albeit with different pathway specificity and effects magnitude. Exercise comprehensively reversed injury-associated effects in the hippocampus across both activated inflammatory and inhibited neuronal pathways, consistent with a return toward the noninjured, homeostatic state. In contrast, the cortex showed a less consistent pattern with more limited attenuation of inflammatory pathway activation and an amplification in the injury-dependent inhibition of select noninflammatory pathways, indicating less effective and potentially detrimental responses to exercise. Exercise intervention beginning 2 weeks after injury and lasting 2 weeks was less effective than exercise continuing for 4 weeks. Exercise initiated at a more delayed timepoint of 6 weeks after injury and continuing for 4 weeks was more effective than that during the acute phase. The delayed paradigm was also more effective than exercise initiated at 10 weeks after injury and continuing for 8 weeks, consistent with hormetic responses in other models and species. Overall, our study delineates regional and interventional parameters, as well as related molecular pathway changes, associated with post-conditioning exercise treatment, which may help inform future translational interventional strategies.

Association Between Omega-3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose-Response Meta-Analysis of Randomized Controlled Trials.

Background Previous results provide supportive but not conclusive evidence for the use of omega-3 fatty acids to reduce blood lipids and prevent events of atherosclerotic cardiovascular disease, but the strength and shape of dose-response relationships remain elusive. Methods and Results This study included 90 randomized controlled trials, reported an overall sample size of 72 598 participants, and examined the association between omega-3 fatty acid (docosahexaenoic acid, eicosapentaenoic acid, or both) intake and blood lipid changes. Random-effects 1-stage cubic spline regression models were used to study the mean dose-response association between daily omega-3 fatty acid intake and changes in blood lipids. Nonlinear associations were found in general and in most subgroups, depicted as J-shaped dose-response curves for low-/high-density lipoprotein cholesterol. However, we found evidence of an approximately linear dose-response relationship for triglyceride and non-high-density lipoprotein cholesterol among the general population and more evidently in populations with hyperlipidemia and overweight/obesity who were given medium to high doses (>2 g/d). Conclusions This dose-response meta-analysis demonstrates that combined intake of omega-3 fatty acids near linearly lowers triglyceride and non-high-density lipoprotein cholesterol. Triglyceride-lowering effects might provide supportive evidence for omega-3 fatty acid intake to prevent cardiovascular events.

Optimal Doses of Specific Antipsychotics for Relapse Prevention in a Nationwide Cohort of Patients with Schizophrenia.

Background and HypothesisOptimal doses of most antipsychotics in the maintenance treatment of schizophrenia are unknown. We aimed to study the risk of severe relapse indicated by rehospitalization for different dose categories of 15 most frequently used antipsychotics in monotherapy in Finland. Study MethodsWe studied the risk of rehospitalization (Adjusted Hazard Ratio, aHR) associated with six antipsychotic monotherapy dose categories (as time-varying dose, measured in defined daily dose, DDDs/day) in a nationwide cohort of persons diagnosed with schizophrenia (n = 61 889), using within-individual analyses to eliminate selection bias. Study ResultsAmong the 15 most widely used antipsychotics, 13 had a U- or J-shaped dose-response curve, showing the lowest risks of relapse for doses of 0.6–<1.1 DDDs/day vs nonuse of antipsychotics. The exceptions were oral perphenazine (aHR = 0.72, 95% CI = 0.68–0.76, <0.6 DDDs/day), and olanzapine-long-acting injectable (LAI), which had the lowest aHR of any antipsychotic (aHR = 0.17, 95% CI = 0.11–0.25, 1.4–<1.6 DDDs/day). Certain risperidone and perphenazine doses <0.9 DDD/day were associated with 21%–45% lower risk of rehospitalization (P < .001) than the standard dose of 0.9–1.1 DDD/day (ie, 5 mg for risperidone and 30 mg for perphenazine). ConclusionsFor most antipsychotics, the risk of severe relapse was the lowest during use of standard dose. Our results suggest that olanzapine LAI is highly effective in dose ranges >0.9 DDD/day, and especially at 1.4–<1.6 DDDs/day (405 mg/4 weeks) associated with substantially lower risk of rehospitalization than any dose of any other antipsychotic. The current WHO standard dose definitions appear to be clearly too high for perphenazine and somewhat too high for risperidone.

Exercise-Related Acute Cardiovascular Events and Potential Deleterious Adaptations Following Long-Term Exercise Training: Placing the Risks Into Perspective-An Update: A Scientific Statement From the American Heart Association.

Epidemiological and biological plausibility studies support a cause-and-effect relationship between increased levels of physical activity or cardiorespiratory fitness and reduced coronary heart disease events. These data, plus the well-documented anti-aging effects of exercise, have likely contributed to the escalating numbers of adults who have embraced the notion that "more exercise is better." As a result, worldwide participation in endurance training, competitive long distance endurance events, and high-intensity interval training has increased markedly since the previous American Heart Association statement on exercise risk. On the other hand, vigorous physical activity, particularly when performed by unfit individuals, can acutely increase the risk of sudden cardiac death and acute myocardial infarction in susceptible people. Recent studies have also shown that large exercise volumes and vigorous intensities are both associated with potential cardiac maladaptations, including accelerated coronary artery calcification, exercise-induced cardiac biomarker release, myocardial fibrosis, and atrial fibrillation. The relationship between these maladaptive responses and physical activity often forms a U- or reverse J-shaped dose-response curve. This scientific statement discusses the cardiovascular and health implications for moderate to vigorous physical activity, as well as high-volume, high-intensity exercise regimens, based on current understanding of the associated risks and benefits. The goal is to provide healthcare professionals with updated information to advise patients on appropriate preparticipation screening and the benefits and risks of physical activity or physical exertion in varied environments and during competitive events.

Inflammatory potential of low doses of airborne fungi from fungal infested damp and dry gypsum boards

This study has investigated the total inflammatory potential (TIP) of low concentration fungal samples from moisture-damaged and fungal infested gypsum boards. The fungal aerosols were generated from damp and dried surfaces, and sampled using filter sampling and liquid impingement. The TIP of the samples was analysed using a granulocyte assay based on differentiated HL60 cells. The study found a tendency to a J-shaped dose-response curve for fungal samples. Low concentrations of fungi were aerosolised from the gypsum boards, and the aerosols were dominated by Aspergillus versicolor and Penicillium chrysogenum. Bacillus infantis and Paenibacillus sp. were found on the gypsum boards, but not recovered in the aerosols. A significant correlation was found between the TIP of diluted and undiluted samples of fungal aerosols. However, diluted samples had a higher TIP than undiluted samples, and no significant association was found between concentration of fungi and the TIP of the samples. This is likely due to the J-shaped dose response curve. The aerosol samples from the dried gypsum boards had a significantly higher TIP compared to aerosols from the damp surfaces. However, the J-shaped dose-response curve weakens the conclusion on the influence of surfaces dampness, sampling time, fungal species or sampling methods. It could, however, be concluded that samples from both damp and dry surfaces induce inflammation in the HL60 cells, despite the low concentration of fungi. Thus, a dried fungal infestation in a building seem still to present a concern for the occupant.

Dose-response behavior of the bacterium Vibrio fischeri exposed to pharmaceuticals and personal care products.

The presence of pharmaceuticals and personal care products (PPCPs) in the environment has become a real and widespread concern in recent years. Therefore, the primary goal of this study was to investigate 20 common and widely used PPCPs to assess their individual and combined effect on an important species in one trophic level, i.e., bacteria. The ecotoxicological effects of PPCPs at two different concentration ranges were determined in the bacterium Vibrio fischeri using Microtox(®) and were statistically analyzed using three models in the GraphPad Prism 6 program for Windows, v.6.03. A four-parameter model best fit the majority of the compounds. The half maximal effective concentration (EC50) of each PPCP was estimated using the best-fitting model and was compared with the results from a recent study. Comparative analysis indicated that most compounds showed the same level of toxicity. Moreover, the stimulatory effects of PPCPs at environmental concentrations (low doses) were assessed. These results indicated that certain compounds have traditional inverted U- or J-shaped dose-response curves, and 55% of them presented a stimulatory effect below the zero effect-concentration point. Effective concentrations of 0 (EC0), 5 (EC5) and 50% (EC50) were calculated for each PPCP as the ecotoxicological points. All compounds that presented narcosis as a mode of toxic action at high doses also exhibited stimulation at low concentrations. The maximum stimulatory effect of a mixture was higher than the highest stimulatory effect of each individually tested compound. Moreover, when the exposure time was increased, the hormetic effect decreased. Hormesis is being increasingly included in dose-response studies because this may have a harmful, beneficial or indifferent effect in an environment. Despite the results obtained in this research, further investigations need to be conducted to elucidate the behavior of PPCPs in aquatic environments.

Bisphenol-A exposures and behavioural aberrations: median and linear spline and meta-regression analyses of 12 toxicity studies in rodents.

Exposures to bisphenol-A, a weak estrogenic chemical, largely used for the production of plastic containers, can affect the rodent behaviour. Thus, we examined the relationships between bisphenol-A and the anxiety-like behaviour, spatial skills, and aggressiveness, in 12 toxicity studies of rodent offspring from females orally exposed to bisphenol-A, while pregnant and/or lactating, by median and linear splines analyses. Subsequently, the meta-regression analysis was applied to quantify the behavioural changes. U-shaped, inverted U-shaped and J-shaped dose-response curves were found to describe the relationships between bisphenol-A with the behavioural outcomes. The occurrence of anxiogenic-like effects and spatial skill changes displayed U-shaped and inverted U-shaped curves, respectively, providing examples of effects that are observed at low-doses. Conversely, a J-dose-response relationship was observed for aggressiveness. When the proportion of rodents expressing certain traits or the time that they employed to manifest an attitude was analysed, the meta-regression indicated that a borderline significant increment of anxiogenic-like effects was present at low-doses regardless of sexes (β)=-0.8%, 95% C.I. -1.7/0.1, P=0.076, at ≤120 μg bisphenol-A. Whereas, only bisphenol-A-males exhibited a significant inhibition of spatial skills (β)=0.7%, 95% C.I. 0.2/1.2, P=0.004, at ≤100 μg/day. A significant increment of aggressiveness was observed in both the sexes (β)=67.9,C.I. 3.4, 172.5, P=0.038, at >4.0 μg. Then, bisphenol-A treatments significantly abrogated spatial learning and ability in males (P<0.001 vs. females). Overall, our study showed that developmental exposures to low-doses of bisphenol-A, e.g. ≤120 μg/day, were associated to behavioural aberrations in offspring.

Cubic Spline Regression of J-shaped Dose-Response Curves with Likelihood-based Assignments of Grouped Exposure Levels

In epidemiological studies that measure the risk at different levels of exposure, the data is often only available for the analyses that summarized the response data in grouped exposure intervals. In typical methods, the midpoints are used as the assigned exposure levels for each interval. Results of the analysis with grouped data may be sensitive to the assignment of the exposure levels. In this paper, we propose a procedure for assessing J-shaped associations based on the likelihood-based assignment of values to grouped intervals of exposure, and applying the cubic spline regression models. Numerical illustrations and comparisons based on simulations showed that the proposed procedure can yield better estimates for curves than those obtained using the typical assignment method based on the midpoints of each interval.

Systems Cancer Biology and the Controlling Mechanisms for the J-Shaped Cancer Dose Response: Towards Relaxing the LNT Hypothesis.

The hormesis phenomena or J-shaped dose response have been accepted as a common phenomenon regardless of the involved biological model, endpoint measured and chemical class/physical stressor. This paper first introduced a mathematical dose response model based on systems biology approach. It links molecular-level cell cycle checkpoint control information to clonal growth cancer model to predict the possible shapes of the dose response curves of Ionizing Radiation (IR) induced tumor transformation frequency. J-shaped dose response curves have been captured with consideration of cell cycle checkpoint control mechanisms. The simulation results indicate the shape of the dose response curve relates to the behavior of the saddle-node points of the model in the bifurcation diagram. A simplified version of the model in previous work of the authors was used mathematically to analyze behaviors relating to the saddle-node points for the J-shaped dose response curve. It indicates that low-linear energy transfer (LET) is more likely to have a J-shaped dose response curve. This result emphasizes the significance of systems biology approach, which encourages collaboration of multidiscipline of biologists, toxicologists and mathematicians, to illustrate complex cancer-related events, and confirm the biphasic dose-response at low doses.

Computational Modeling of Signaling Pathways Mediating Cell Cycle Checkpoint Control and Apoptotic Responses to Ionizing Radiation-Induced DNA Damage

The shape of dose response of ionizing radiation (IR) induced cancer at low dose region, either linear non-threshold or J-shaped, has been a debate for a long time. This dose response relationship can be influenced by built-in capabilities of cells that minimize the fixation of IR-mediated DNA damage as pro-carcinogenic mutations. Key capabilities include sensing of damage, activation of cell cycle checkpoint arrests that provide time needed for repair of the damage as well as apoptosis. Here we describe computational modeling of the signaling pathways that link sensing of DNA damage and checkpoint arrest activation/apoptosis to investigate how these molecular-level interactions influence the dose response relationship for IR induced cancer. The model provides qualitatively accurate descriptions of the IR-mediated activation of cell cycle checkpoints and the apoptotic pathway, and of time-course activities and dose response of relevant regulatory proteins (e.g. p53 and p21). Linking to a two-stage clonal growth cancer model, the model described here successfully captured a monotonically increasing to a J-shaped dose response curve and identified one potential mechanism leading to the J-shape: the cell cycle checkpoint arrest time saturates with the increase of the dose.

Changing the Risk Paradigms can be Good for Our Health: J-Shaped, Linear and Threshold Dose-Response Models

Both the linear (at low doses)-no-threshold (LNT) and the threshold models (S-shapes) dose-response lead to no benefit from low exposure. We propose three new models that allow and include, but do not require - unlike LNT and S-shaped models - this strong assumption. We also provide the means to calculate benefits associated with bi-phasic biological behaviors, when they occur and propose:THREE HORMETIC (PHASIC) MODELS: the J-shaped, inverse J-shaped, the min-max, andMethod for calculating the direct benefits associated with the J and inverse J-shaped models.The J-shaped and min-max models for mutagens and carcinogenic agents include an experimentally justified repair stage for toxic and carcinogenic damage. We link these to stochastic transition models for cancer and show how abrupt transitions in cancer hazard rates, as functions of exposure concentrations and durations, can emerge naturally in large cell populations even when the rates of cell-level events increase smoothly (e.g., proportionally) with concentration. In this very general family of models, J-shaped dose-response curves emerge. These results are universal, i.e., independent of specific biological details represented by the stochastic transition networks. Thus, using them suggests a more complete and realistic way to assess risks at low doses or dose-rates.

Effects of ethanol on the shoaling behavior of zebrafish (danio rerio).

Ethanol (EtOH) often has stimulatory effects at low doses and inhibitory effects at high doses, affecting behavior and physiology of many organisms in a non-linear manner suggestive of hormesis. Zebrafish (Danio rerio) shoaling was studied in adult fish exposed to one of five different EtOH concentrations (v/v): 0.0% control, 0.125%, 0.25%, 0.5%, and 1.0%. Digital photographs of groups of four fish were taken every 2 min, with each trial lasting a total of 12 min. The median nearest neighbor distance and shoal area were calculated for each photograph. Exposure to 1.0% EtOH inhibited shoaling. In contrast, as predicted from hormesis, shoaling was significantly tighter (as measured by nearest neighbor distance) at low concentrations (0.125%, 0.25%) compared to the control, and a J-shaped dose-response curve was present. A similar pattern occurred for shoal area, but in this case the only statistically significant differences were between the high concentration and all others.

Modeling dose-Response at Low dose: A Systems Biology Approach for Ionization Radiation

For ionization radiation (IR) induced cancer, a linear non-threshold (LNT) model at very low doses is the default used by a number of national and international organizations and in regulatory law. This default denies any positive benefit from any level of exposure. However, experimental observations and theoretical biology have found that both linear and J-shaped IR dose-response curves can exist at those very low doses. We develop low dose J-shaped dose-response, based on systems biology, and thus justify its use regarding exposure to IR. This approach incorporates detailed, molecular and cellular descriptions of biological/toxicological mechanisms to develop a dose-response model through a set of nonlinear, differential equations describing the signaling pathways and biochemical mechanisms of cell cycle checkpoint, apoptosis, and tumor incidence due to IR. This approach yields a J-shaped dose response curve while showing where LNT behaviors are likely to occur. The results confirm the hypothesis of the J-shaped dose response curve: the main reason is that, at low-doses of IR, cells stimulate protective systems through a longer cell arrest time per unit of IR dose. We suggest that the policy implications of this approach are an increasingly correct way to deal with precautionary measures in public health.

Associations between Beer, Wine, and Liquor Consumption and Lung Cancer Risk: A Meta-analysis

Epidemiologic studies suggest that the effect on lung cancer risk may be different for beer, wine, and liquor. We conducted dose-specific meta-analyses and dose-response meta-regression to summarize findings from the current literature on the association between consumption of beer, wine, or liquor and lung cancer risk. Average beer consumption of one drink or greater per day was associated with an increased risk of lung cancer [relative risk (RR), 1.23; 95% confidence interval (95% CI), 1.06-1.41]. This association was observed in both men and women, although it was only significant in men. A J-shaped dose-response curve was suggested for beer intake. An inverse association was observed for both average wine consumption of less than one drink per day (RR, 0.77; 95% CI, 0.59-1.00) and one drink or greater per day (RR, 0.78; 95% CI, 0.60-1.02) in the drinking range incurred in the source studies. Average liquor consumption of one drink or greater per day was found to be associated with increased risk in men (RR, 1.33; 95% CI, 1.10-1.62). No association was observed for liquor drinking in women. The presence of heterogeneity between studies was detected. Study design, country, gender, adjustment factors, and lung cancer histologic type were not significant predictors of the heterogeneity. The results from this meta-analysis suggest that high consumption of beer and liquors may be associated with increased lung cancer risk, whereas modest wine consumption may be inversely associated with risk. More research with improved control of confounding is needed to confirm these findings and to establish the dose-response relationship, particularly risk at high consumption levels.

Health risks of low photon energy imaging

The major health risk associated with low photon energy imaging is thought to be the induction of cancer as a consequence of the radiation exposure and this is the focus of this paper. Low photon energy imaging typically involves exposure to a low dose (<50 mGy) of low linear energy transfer (LET) radiation delivered at high dose-rate. Since epidemiologic data cannot provide an accurate assessment of risk at the doses used in imaging, risk estimates are currently made by fitting a linear response to intermediate and high dose data for cancer induction in radiation-exposed human populations. This method assumes a linear no-threshold (LNT) response and implies that no dose of radiation is safe. This assumption is not borne out by many laboratory studies of cancer-related endpoints that would suggest that the risk at low doses is much less than would be estimated from linear extrapolation from intermediate to high doses. It is also well recognised that the dose-response from many epidemiologic studies could equally well be fit by threshold models. Through the study of radiation-induced neoplastic transformation in vitro J-shaped dose-response curves for a variety of low LET radiations, including those used in low photon energy imaging, have been demonstrated. The relative risks calculated from this data compare remarkably well with those for breast cancer and leukemia incidence in radiation-exposed populations. From this it is concluded that the LNT hypothesis is likely to overestimate the risk of cancer induction by low photon energy imaging, at least for certain tumors.

Alcohol consumption and risk of leukemia: A multicenter case–control study

A population-based case–control study of 649 leukemia cases and 1771 controls carried out in 11 Italian areas, offered the opportunity to evaluate the relationship between alcohol consumption and leukemia risk. For all leukemias, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL), we found a non-significantly inverse association for moderate levels of total alcohol and wine intake, but increased risks at high levels, with, in most cases, significant trend effects (odd ratios (OR) for all leukemias in the lowest quartile of total alcohol consumption [0.1–9.0 g/day of ethanol] versus never-drinker = 0.73; 95% confidence intervals (95% CI) = 0.51–1.03; OR in the highest quartile [> 31.7 g/day] = 1.15; 95% CI = 0.82–1.63; p of the linear trend test = 0.007). For chronic myeloid leukemia (CML), we found a non-significantly positive association for all levels of total alcohol and wine intake, and a significant positive linear trend effect ( p = 0.03) for wine intake (OR for 0.1–9.0 g/day of ethanol intake from wine = 1.34; 95% CI = 0.61–2.94; OR in the highest quartile of wine intake [> 27.7 g/day] = 2.13; 95% CI = 1.01–4.50). No consistent dose–response was detected analysing duration of alcohol consumption for any leukemia subtypes. In conclusion, even though our study did not show a clear association between alcohol intake and leukemia risk, some of the patterns of the risk estimates (a possible J-shaped dose–response curve between alcohol intake and ALL, AML, and CLL risks, and the positive association between alcohol and CML), may be suggestive.

Universality of J-Shaped and U-Shaped Dose-Response Relations as Emergent Properties of Stochastic Transition Systems

Dose-response data for many chemical carcinogens exhibit multiple apparent concentration thresholds. A relatively small increase in exposure concentration near such a threshold disproportionately increases incidence of a specific tumor type. Yet, many common mathematical models of carcinogenesis do not predict such threshold-like behavior when model parameters (e.g., describing cell transition rates) increase smoothly with dose, as often seems biologically plausible. For example, commonly used forms of both the traditional Armitage-Doll and multistage (MS) models of carcinogenesis and the Moolgavkar-Venzon-Knudson (MVK) two-stage stochastic model of carcinogenesis typically yield smooth dose-response curves without sudden jumps or thresholds when exposure is assumed to increase cell transition rates in proportion to exposure concentration.This paper introduces a general mathematical modeling framework that includes the MVK and MS model families as special cases, but that shows how abrupt transitions in cancer hazard rates, considered as functions of exposure concentrations and durations, can emerge naturally in large cell populations even when the rates of cell-level events increase smoothly (e.g., proportionally) with concentration. In this framework, stochastic transitions of stem cells among successive events represent exposure-related damage. Cell proliferation, cell killing and apoptosis can occur at different stages. Key components include: An effective number of stem cells undergoing active cycling and hence vulnerable to stochastic transitions representing somatically heritable transformations. (These need not occur in any special linear order, as in the MS model.)A random time until the first malignant stem cell is formed. This is the first order-statistic, T = min{T1, T2, ..., Tn} of n random variables, interpreted as the random times at which each of n initial stem cells or their progeny first become malignant.A random time for a normal stem cell to complete a full set of transformations converting it to a malignant one. This is interpreted very generally as the first passage time through a network of stochastic transitions, possibly with very many possible paths and unknown topology.In this very general family of models, threshold-like (J-shaped or multi-threshold) dose-response nonlinearities naturally emerge even without cytotoxicity, as consequences of stochastic phase transition laws for traversals of random transition networks. With cytotoxicity present, U-shaped as well as J-shaped dose-response curves can emerge. These results are universal, i.e., independent of specific biological details represented by the stochastic transition networks.

Dioxin Cancer Risk — Example of Hormesis?

A recent case-control study implied an inverse correlation between the measured body burden of dioxins (polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, PCDD/F) and the risk of soft tissue sarcoma in normal population exposed to dioxins mainly via food. The surprising result could not be explained by biases or confounding. There is no a priori confounding by occupational chemicals in a random sample from general population, but exposures to other lipid soluble chemicals with similar sources might be expected to associate with that of dioxins. One such group is polychlorinated biphenyls (PCB). Therefore three most relevant dioxin-like PCB compounds PCB 77, PCB 126, and PCB 169 were now analyzed from the same patients. Cases were 110 soft-tissue sarcoma patients undergoing surgery for their disease, and referents were 227 patients operated for appendicitis. Dioxin and PCB concentrations were analyzed from subcutaneous fat samples by high-resolution gas chromatography-mass spectrometry and TCDD equivalent concentrations (WHO-TEq) were calculated by using toxicity equivalency factors of WHO. The highest risk of sarcoma was found in the septile with the lowest body burden of sum WHO-TEq, and the differences of septiles 2 and 6 from septile 1 were statistically significant. If soft sarcoma risk is true at high occupational levels of dioxins, the provocative result suggests that a possibility of a J-shaped dose-response curve should be taken into consideration and studied further. This is also supported by the similar J-shaped dose responses in animal studies.

The U.S. EPA Science Advisory Board Evaluation (2001) of the EPA Dioxin Reassessment

The U.S. Environmental Protection Agency (EPA) began a “reassessment” of the risks posed by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD or dioxin) and related chemicals in 1991 and issued an interim report in 1994. In 1995, the Science Advisory Board (SAB) reviewed this document and requested revisions. After considerable additional work, EPA issued its final draft report in September 2000. A new EPA SAB reviewed this draft and issued its recommendations in June 2001. This group of scientists offered suggestions to EPA on the following topics, which are discussed in some detail in this article: classification as a “known” human carcinogen, how to estimate the carcinogenic potency, the possible significance of the noncancer hazard, the proper dose metric for cancer and noncancer effects, the uncertainties inherent in the toxicity equivalency factor approach, use of the margin of exposure approach, adequacy of the exposure assessment, body burden calculations, risks to breast feeding children, nonmonotonic responses (U- or J-shaped dose–response curves, or hormetic effect), the possible significance of naturally occurring dioxin-like chemicals, and risks to special populations. The basis for the recommendations, as generally presented in the SAB report, is described here. A discussion of some of the recently published work within the regulatory and scientific communities that has been issued since the SAB report is also presented.

Threshold dose response for tumor induction by genotoxic carcinogens modeled via cell-cycle delay.

Dose-response relationships for tumor induction in animal bioassays for carcinogenicity are often postulated to include thresholds, particularly for nongenotoxic chemicals that increase the rate of cell proliferation at high doses. In this report, thresholds are postulated also for genotoxic carcinogens. The hypothesis is based on the idea of a delay of the cell cycle induced by low-level DNA damage and an acceleration at cytotoxic dose levels, thus resulting in a J-shaped (or U-shaped) dose response for cell turnover. Calculations were based on the 2-stage clonal expansion model of carcinogenesis. The background values chosen for the model parameters resulted in a 10.5% "spontaneous" 2-year cumulative tumor incidence. Using this as a starting point, a decrease by 3, 10, and 30% in the rates of cell turnover resulted in a decrease in the spontaneous tumor incidence to 9.4, 7.1 and 3.0%, respectively. Dose-responses with J-shaped curves for the rates of cell birth and death were modeled by shifted quadratic functions reaching the minimum at dose 1. Combinations with linearly increasing mutation rates also generated, under certain conditions, J-shaped dose-response curves for tumor incidence. As an example, for a 30% increase in mutation rates and a 10% decrease in cell turnover rates (both at dose 1), the dose-response curve showed an initial decrease of tumor incidence below the spontaneous rate, a reversion to the background value at 0.8 dose units, and an increase thereafter. The 0.8 dose could be considered to represent the "threshold dose." The approach presented might reconcile opposing views on thresholds on a biologically plausible mechanistic basis, and show a way for the quantitative estimation of threshold doses.