Risk Assessment of Laboratory Rats and Mice Chronically Exposed to Formaldehyde Vapors

Experimental data from the Chemical Industry Institute of Toxicology (CIIT) are used to estimate the risk of squamous cell carcinoma of the nasal cavity in Fischer 344 (F344) rats over a range of ambient air concentrations of formaldehyde that includes current exposure guidelines for the workplace and home. These values are presented as a best estimate envelope obtained from five mathematical dose-response formulation. The response of Sprague-Dawley (SD) rats dosed at 15 ppm in a separate study at New York University is consistent with the predicted lifetime response for F344 rats at a slightly lower concentration (13-14 ppm). A dose-related mortality effect beyond what is attributable to the occurrence of nasal carcinomas is found in F344 rats at all CIIT exposure levels (2, 6, and 15 ppm). There is no evidence of a mortality effect in B6C3F1 mice of the CIIT study, and data for SD rats of the NYU experiment are inconclusive. In the CIIT study, rats exposed to 15 ppm exhibited a high incidence of nasal cavity squamous cell carcinomas and polypoid adenomas. Polypoid adenomas were also observed with increased incidences at 2 ppm and 6 ppm. Statistical comparisons with matched controls, and the low historical rate of spontaneous occurrence both suggest that polypoid adenomas may be a risk to F344 rats at exposure levels below the current Occupational Safety and Health Administration (OSHA) standard of 3 ppm. Squamous cell carcinomas were observed in two mice exposed to 15 ppm. This finding may be biologically significant since this tumor is rare and has not been previously reported in 4932 untreated B6C3F1 mice from recent National Toxicology Program (NTP) feeding studies.     

Carcinogenicity Studies on MTBE: Critical Review and Interpretation

Chronic inhalation of toxic concentrations of MTBE caused renal tubular cell neoplasms in male Fischer 344 rats and hepatocellular adenomas in female CD-1 mice. In Sprague-Dawley rats the oral administration of MTBE was associated with increased incidences of Leydig cell tumors and of lymphomas and leukemias (combined) in males and females, respectively. Neither lymphomas nor leukemias were individually increased in treated females. Leydig cell tumors are common in rats and do not predict human responses to drugs and chemicals. Neither MTBE nor its metabolite, t -butyl alcohol, possess mutagenic potential and a second metabolite, formaldehyde, is mutagenic in vitro but in vivo results are equivocal. MTBE-induced neoplasms are most likely produced through a nongenetic mechanism which requires chronic exposure to toxic doses. Because of the intense odor (and taste) of MTBE, humans will not tolerate either air or water concentrations sufficient to produce the cytotoxic precursors required to promote cellular proliferation.     

Statistical Modeling of Animal Bioassay Data with Variable Dosing Regimens: Example—Vinyl Chloride

We consider animal bioassay experiments with variable dosing regimens in which groups of animals are dosed beginning at different ages and for varying durations. Two response models are discussed and then applied to data from an experiment on vinyl chloride exposure of F-344 rats, B6C3F1 and Swiss CD-1 mice, and Syrian Golden hamsters. The multistage model of Armitage and Doll, as extended by Whittemore, Day and Brown, and Crump and Howe, is used to estimate the dose effect on the ordered stages of tumor development. The data for all endpoints and species/strains examined consistently indicate a predominant effect on the first stage, suggesting that vinyl chloride is primarily a tumor initiator. This is consistent with evidence from two-stage experiments on this chemical. The second response model, new to this article, adjusts for survival nonparametrically. It is used to test for an age difference in susceptibility, to evaluate alternative exposure durations, and to compare the effectiveness of alternative dosing regimens for detecting carcinogenicity.     

Uncertainties in the CIIT Model for Formaldehyde-Induced Carcinogenicity in the Rat: A Limited Sensitivity Analysis–I

Scientists at the CIIT Centers for Health Research (Conolly et al., 2000, 2003; Kimbell et al., 2001a, 2001b) developed a two-stage clonal expansion model of formaldehyde-induced nasal cancers in the F344 rat that made extensive use of mechanistic information. An inference of their modeling approach was that formaldehyde-induced tumorigenicity could be optimally explained without the role of formaldehyde's mutagenic action. In this article, we examine the strength of this result and modify select features to examine the sensitivity of the predicted dose response to select assumptions. We implement solutions to the two-stage cancer model that are valid for nonhomogeneous models (i.e., models with time-dependent parameters), thus accounting for time dependence in variables. In this reimplementation, we examine the sensitivity of model predictions to pooling historical and concurrent control data, and to lumping sacrificed animals in which tumors were discovered incidentally with those in which death was caused by the tumors. We found the CIIT model results were not significantly altered with the nonhomogeneous solutions. Dose-response predictions below the range of exposures where tumors occurred in the bioassays were highly sensitive to the choice of control data. In the range of exposures where tumors were observed, the model attributed up to 74% of the added tumor probability to formaldehyde's mutagenic action when our reanalysis restricted the use of the National Toxicology Program (NTP) historical control data to only those obtained from inhalation exposures. Model results were insensitive to hourly or daily temporal variations in DNA protein cross-link (DPX) concentration, a surrogate for the dose-metric linked to formaldehyde-induced mutations, prompting us to utilize weekly averages for this quantity. Various other biological and mathematical uncertainties in the model have been retained unmodified in this analysis. These include model specification of initiated cell division and death rates, and uncertainty and variability in the dose response for cell replication rates, issues that will be considered in a future paper.     

Cell Proliferation and Formaldehyde-Induced Respiratory Carcinogenesis

Formaldehyde is a nasal carcinogen in the rat but the cancer risk this chemical poses for humans remains to be determined. Formaldehyde induces nonlinear, concentration-dependent increases in nasal epithelial cell proliferation and DNA-protein cross-link formation following short-term exposure. Presented in this review are results from a mechanistically based formaldehyde inhalation study in which an important endpoint was the measurement of cell proliferation indices in target sites for nasal tumor induction. Male Fischer 344 rats were exposed to 0, 0.7, 2, 6, 10, or 15 ppm formaldehyde for up to 2 years (6 hr/day, 5 day/week). Statistically significant increases in cell proliferation were confined to the 10 and 15 ppm groups, which remained elevated throughout the study. The concentration-dependent increases in cell proliferation correlated strongly with the tumor response curve, supporting the proposal that sustained increases in cell proliferation are an important component of formaldehyde carcinogenesis. The nonlinearity observed in formaldehyde-induced rodent nasal cancer is consistent with a high-concentration effect of regenerative cell proliferation of the target organ coupled with the genotoxic effects of formaldehyde. Cell kinetic data from these studies provide important information that may be utilized in the assessment of risk for humans exposed to formaldehyde.     

Estimates of the Number of Liver Carcinogens in Bioassays Conducted by the National Toxicology Program

Estimates were made of the numbers of liver carcinogens in 390 long-term bioassays conducted by the National Toxicology Program (NTP). These estimates were obtained from examination of the global pattern of p-values obtained from statistical tests applied to individual bioassays. Representative estimates of the number of liver carcinogens (90% confidence interval in parentheses) obtained in our analysis compared to NTP's determination are as follows: female rats—49 (23, 76), NTP = 30; male rats—88 (59, 116), NTP = 35; female mice—131 (105, 157), NTP = 81; male mice—100 (73, 126), NTP = 61; overall—166 (135, 197), NTP = 108. The estimator from which these estimates were obtained is biased low by an unknown amount. Consequently, this study provides persuasive evidence of the existence of more rodent liver carcinogens than were identified by the NTP.     

Categorizing Mistaken False Positives in Regulation of Human and Environmental Health

One of the concerns often voiced by critics of the precautionary principle is that a widespread regulatory application of the principle will lead to a large number of false positives (i.e., over-regulation of minor risks and regulation of nonexisting risks). The present article proposes a general definition of a regulatory false positive, and seeks to identify case studies that can be considered authentic regulatory false positives. Through a comprehensive review of the science policy literature for proclaimed false positives and interviews with authorities on regulation and the precautionary principle we identified 88 cases. Following a detailed analysis of these cases, we found that few of the cases mentioned in the literature can be considered to be authentic false positives. As a result, we have developed a number of different categories for these cases of "mistaken false positives," including: real risks, "The jury is still out," nonregulated proclaimed risks, "Too narrow a definition of risk," and risk-risk tradeoffs. These categories are defined and examples are presented in order to illustrate their key characteristics. On the basis of our analysis, we were able to identify only four cases that could be defined as regulatory false positives in the light of today's knowledge and recognized uncertainty: the Southern Corn Leaf Blight, the Swine Flu, Saccharin, and Food Irradiation in relation to consumer health. We conclude that concerns about false positives do not represent a reasonable argument against future application of the precautionary principle.     

Extrapolation of Carcinogenicity Between Species: Qualitative and Quantitative Factors

Prediction of human cancer risk from the results of rodent bioassays requires two types of extrapolation: a qualitative extrapolation from short-lived rodent species to long-lived humans, and a quantitative extrapolation from near-toxic doses in the bioassay to low-level human exposures. Experimental evidence on the accuracy of prediction between closely related species tested under similar experimental conditions (rats, mice, and hamsters) indicates that: (1) if a chemical is positive in one species, it will be positive in the second species about 75% of the time; however, since about 50% of test chemicals are positive in each species, by chance alone one would expect a predictive value between species of about 50%. (2) If a chemical induces tumors in a particular target organ in one species, it will induce tumors in the same organ in the second species about 50% of the time. Similar predictive values are obtained in an analysis of prediction from humans to rats or from humans to mice for known human carcinogens. Limitations of bioassay data for use in quantitative extrapolation are discussed, including constraints on both estimates of carcinogenic potency and of the dose-response in experiments with only two doses and a control. Quantitative extrapolation should be based on an understanding of mechanisms of carcinogenesis, particularly mitogenic effects that are present at high and not low doses.     

Monte Carlo Simulation of Rodent Carcinogenicity Bioassays

In this paper we describe a simulation, by Monte Carlo methods, of the results of rodent carcinogenicity bioassays. Our aim is to study how the observed correlation between carcinogenic potency (beta or 1n2/TD50) and maximum tolerated dose (MTD) arises, and whether the existence of this correlation leads to an artificial correlation between carcinogenic potencies in rats and mice. The validity of the bioassay results depends upon, among other things, certain biases in the experimental design of the bioassays. These include selection of chemicals for bioassay and details of the experimental protocol, including dose levels. We use as variables in our simulation the following factors: (1) dose group size, (2) number of dose groups, (3) tumor rate in the control (zero-dose) group, (4) distribution of the MTD values of the group of chemicals as specified by the mean and standard deviation, (5) the degree of correlation between beta and the MTD, as given by the standard deviation of the random error term in the linear regression of log beta on log (1/MTD), and (6) an upper limit on the number of animals with tumors. Monte Carlo simulation can show whether the information present in the existing rodent bioassay database is sufficient to reject the validity of the proposed interspecies correlations at a given level of stringency. We hope that such analysis will be useful for future bioassay design, and more importantly, for discussion of the whole NCI/NTP program.     

Benchmark Dose Risk Assessment for Formaldehyde Using Airflow Modeling and a Single-Compartment, DNA-Protein Cross-Link Dosimetry Model to Estimate Human Equivalent Doses

Formaldehyde induced squamous-cell carcinomas in the nasal passages of F344 rats in two inhalation bioassays at exposure levels of 6 ppm and above. Increases in rates of cell proliferation were measured by T. M. Monticello and colleagues at exposure levels of 0.7 ppm and above in the same tissues from which tumors arose. A risk assessment for formaldehyde was conducted at the CIIT Centers for Health Research, in collaboration with investigators from Toxicological Excellence in Risk Assessment (TERA) and the U.S. Environmental Protection Agency (U.S. EPA) in 1999. Two methods for dose-response assessment were used: a full biologically based modeling approach and a statistically oriented analysis by benchmark dose (BMD) method. This article presents the later approach, the purpose of which is to combine BMD and pharmacokinetic modeling to estimate human cancer risks from formaldehyde exposure. BMD analysis was used to identify points of departure (exposure levels) for low-dose extrapolation in rats for both tumor and the cell proliferation endpoints. The benchmark concentrations for induced cell proliferation were lower than for tumors. These concentrations were extrapolated to humans using two mechanistic models. One model used computational fluid dynamics (CFD) alone to determine rates of delivery of inhaled formaldehyde to the nasal lining. The second model combined the CFD method with a pharmacokinetic model to predict tissue dose with formaldehyde-induced DNA-protein cross-links (DPX) as a dose metric. Both extrapolation methods gave similar results, and the predicted cancer risk in humans at low exposure levels was found to be similar to that from a risk assessment conducted by the U.S. EPA in 1991. Use of the mechanistically based extrapolation models lends greater certainty to these risk estimates than previous approaches and also identifies the uncertainty in the measured dose-response relationship for cell proliferation at low exposure levels, the dose-response relationship for DPX in monkeys, and the choice between linear and nonlinear methods of extrapolation as key remaining sources of uncertainty.     

考虑无缺陷退货下零售商转运的供应链回购契约研究

针对由单个供应商和同一连锁企业的两个零售商组成的供应链系统中无缺陷退货问题。在随机需求下,假设零售商努力水平与无缺陷退货率成反比,以及两个零售商之间可以相互进行库存转运,建立了期望收益决策模型。通过比较集中决策和分散决策下零售商订货量及各方期望利润,确定了零售商最优订货量和最优努力水平,并提出了改进的差异化回购契约,算例分析表明,改进的差异化回购契约能够达到供应链协调。     

Extended Analysis and Evidence Integration of Chloroprene as a Human Carcinogen

β-Chloroprene is used in the production of polychloroprene, a synthetic rubber. In 2010, Environmental Protection Agency (EPA) published the Integrated Risk Information System “Toxicological Review of Chloroprene,” concluding that chloroprene was “likely to be carcinogenic to humans.” This was based on findings from a 1998 National Toxicology Program (NTP) study showing multiple tumors within and across animal species; results from occupational epidemiological studies; a proposed mutagenic mode of action; and structural similarities with 1,3-butadiene and vinyl chloride. Using mouse data from the NTP study and assuming a mutagenic mode of action, EPA calculated an inhalation unit risk (IUR) for chloroprene of 5 × 10⁻⁴ per µg/m³. This is among the highest IURs for chemicals classified by IARC or EPA as known or probable human carcinogens and orders of magnitude higher than the IURs for carcinogens such as vinyl chloride, benzene, and 1,3-butadiene. Due to differences in pharmacokinetics, mice appear to be uniquely responsive to chloroprene exposure compared to other animals, including humans, which is consistent with the lack of evidence of carcinogenicity in robust occupational epidemiological studies. We evaluated and integrated all lines of evidence for chloroprene carcinogenicity to assess whether the 2010 EPA IUR could be scientifically substantiated. Due to clear interspecies differences in carcinogenic response to chloroprene, we applied a physiologically based pharmacokinetic model for chloroprene to calculate a species-specific internal dose (amount metabolized/gram of lung tissue) and derived an IUR that is over 100-fold lower than the 2010 EPA IUR. Therefore, we recommend that EPA's IUR be updated.     

Correlation of Noncancer Benchmark Doses in Short‐ and Long‐Term Rodent Bioassays

This study investigated whether, in the absence of chronic noncancer toxicity data, short‐term noncancer toxicity data can be used to predict chronic toxicity effect levels by focusing on the dose–response relationship instead of a critical effect. Data from National Toxicology Program (NTP) technical reports have been extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Best‐fit, minimum benchmark dose (BMD), and benchmark dose lower limits (BMDLs) have been modeled for all NTP pathologist identified significant nonneoplastic lesions, final mean body weight, and mean organ weight of 41 chemicals tested by NTP between 2000 and 2012. Models were then developed at the chemical level using orthogonal regression techniques to predict chronic (two years) noncancer health effect levels using the results of the short‐term (three months) toxicity data. The findings indicate that short‐term animal studies may reasonably provide a quantitative estimate of a chronic BMD or BMDL. This can allow for faster development of human health toxicity values for risk assessment for chemicals that lack chronic toxicity data.     

How bad are the effects of bad leaders? A meta-analysis of destructive leadership and its outcomes

While the focus on constructive leadership still dominates leadership research, an increasing number of studies investigate different forms of destructive leadership. This meta-analysis integrates different conceptualizations of destructive leadership and analyzes the relationship between destructive leadership and outcome variables. The search for articles yielded more than 200 studies of which 57 could be included in the meta-analysis. Results indicate the expected negative correlations with positive followers' outcomes and behaviors (e.g., attitudes towards the leader, well-being, and individual performance) and positive correlations with negative outcomes (e.g., turnover intention, resistance towards the leader, counterproductive work behavior). As expected, the highest correlation arises between destructive leadership and attitudes towards the leader. Surprisingly, the next highest correlation was found between destructive leadership and counterproductive work behavior. After discussing the results, an agenda for future research is proposed. Given the negative impact of destructive leadership, more knowledge is especially necessary regarding what triggers destructive leadership.     

Effects of Positive and Negative Feedback Sequence on Work Performance and Emotional Responses

Performance feedback has been broadly used within Organizational Behavior Management. However, the specifics regarding the most effective type of feedback still merits careful investigation, including the use of positive and negative sequences of feedback. The current study randomly assigned participants to receive one of the following sequences: (a) positive-positive feedback, (b) positive-negative feedback, (c) negative-positive feedback, and (d) negative-negative feedback. Uniform feedback delivery resulted in higher performance, although inconsistent feedback resulted in lessened negative emotional responses. Recommendations on whether to deliver positive or negative feedback in isolation or combination may depend upon the outcomes currently being prioritized by the organization.     

Testing and Characterizing Properties of Nonadditive Measures Through Violations of the Sure‐Thing Principle

In expected utility theory, risk attitudes are modeled entirely in terms of utility. In the rank‐dependent theories, a new dimension is added: chance attitude, modeled in terms of nonadditive measures or nonlinear probability transformations that are independent of utility. Most empirical studies of chance attitude assume probabilities given and adopt parametric fitting for estimating the probability transformation. Only a few qualitative conditions have been proposed or tested as yet, usually quasi‐concavity or quasi‐convexity in the case of given probabilities. This paper presents a general method of studying qualitative properties of chance attitude such as optimism, pessimism, and the “inverse‐S shape” pattern, both for risk and for uncertainty. These qualitative properties can be characterized by permitting appropriate, relatively simple, violations of the sure‐thing principle. In particular, this paper solves a hitherto open problem: the preference axiomatization of convex (“pessimistic” or “uncertainty averse”) nonadditive measures under uncertainty. The axioms of this paper preserve the central feature of rank‐dependent theories, i.e. the separation of chance attitude and utility.     

Ambiguous carcinogens and their regulation

Examination of five animal and one human studies suggest that certain agents increase the incidence of some cancers but simultaneously reduce the incidence of other cancers. Yellow die #3, for example, sharply increases the incidence of liver tumors but practically eliminates naturally occurring leukemia/lymphoma in F-344 male rates. Such ambiguity in the action of presumed carcinogens suggests that caution must be used by regulatory bodies in proscribing suspected carcinogens, or even in recommending changes in lifestyle or dietary habits as a means of reducing incidence of cancer.     

Quantitative Cancer Risk Estimation for Formaldehyde

Of primary concern are irreversible effects, such as cancer induction, that formaldehyde exposure could have on human health. Dose-response data from human exposure situations would provide the most solid foundation for risk assessment, avoiding problematic extrapolations from the health effects seen in nonhuman species. However, epidemiologic studies of human formaldehyde exposure have provided little definitive information regarding dose-response. Reliance must consequently be placed on laboratory animal evidence. An impressive array of data points to significantly nonlinear relationships between rodent tumor incidence and administered dose, and between target tissue dose and administered dose (the latter for both rodents and Rhesus monkeys) following exposure to formaldehyde by inhalation. Disproportionately less formaldehyde binds covalently to the DNA of nasal respiratory epithelium at low than at high airborne concentrations. Use of this internal measure of delivered dose in analyses of rodent bioassay nasal tumor response yields multistage model estimates of low-dose risk, both point and upper bound, that are lower than equivalent estimates based upon airborne formaldehyde concentration. In addition, risk estimates obtained for Rhesus monkeys appear at least 10-fold lower than corresponding estimates for identically exposed Fischer-344 rats.