Randomized Phase 3 trial demonstrating high efficacy, favourable safety and convenience of a novel calcipotriol and betamethasone dipropionate cream for the treatment of psoriasis.

BACKGROUND: The fixed dose combination of calcipotriene (CAL) and betamethasone dipropionate (BDP) is a well-established topical treatment option for psoriasis based on strong scientific rationale for the single agents having complementary efficacy and safety. CAL/BDP PAD-cream is an easily spreadable cream based on PAD Technology™, an innovative formulation and drug delivery system. OBJECTIVES AND METHODS: A Phase 3, multicentre, randomized, investigator-blind, active and vehicle-controlled trial enrolling 490 patients with mild to moderate psoriasis according to the Physician Global Assessment (PGA) scale was conducted in three European countries. Products were applied once daily for 8 weeks. The aim of the trial was to evaluate the efficacy and safety of CAL/BDP PAD-cream as well as treatment acceptability compared to CAL/BDP gel and PAD-cream vehicle. Primary endpoint was percentage change in modified Psoriasis Area and Severity Index (mPASI) from baseline to Week 8. RESULTS: The percentage mean change from baseline to Week 8 in mPASI for CAL/BDP PAD-cream (67.5%) was superior compared to PAD-cream vehicle (11.7%; p < 0.0001) and non-inferior to CAL/BDP gel (63.5%). The proportion of patients achieving PGA treatment success (at least two-step improvement to clear or almost clear) after 8 weeks was superior for CAL/BDP PAD-cream (50.7%) compared to PAD-cream vehicle (6.1%, p < 0.0001) and statistically significantly greater than CAL/BDP gel (42.7%, p = 0.0442). Patient-reported psoriasis treatment convenience score (PTCS) for CAL/BDP PAD-cream was rated superior to CAL/BDP gel at Week 8 (p < 0.0001) and the mean change in DLQI from baseline to Week 8 improved statistically significantly more in the CAL/BDP PAD-cream group compared to both PAD-cream vehicle (p < 0.0001) and CAL/BDP gel (p = 0.0110). Safety assessments during the trial demonstrated that CAL/BDP PAD-cream was well-tolerated. CONCLUSION: CAL/BDP PAD-cream is a novel topical treatment of psoriasis that has a high efficacy and a favourable safety profile combined with a superior patient-reported treatment convenience.

Osteoporosis identification among previously undiagnosed individuals with vertebral fractures.

Because osteoporosis is under-recognized in patients with vertebral fractures, we evaluated characteristics associated with osteoporosis identification. Most patients with vertebral fractures did not receive evaluation or treatment for osteoporosis. Black, younger, and male participants were particularly unlikely to have had recognized osteoporosis, which could increase their risk of negative outcomes. INTRODUCTION: Vertebral fractures may be identified on imaging but fail to prompt evaluation for osteoporosis. Our objective was to evaluate characteristics associated with clinical osteoporosis recognition in patients who had vertebral fractures detected on their thoracolumbar spine imaging reports. METHODS: We prospectively identified individuals who received imaging of the lower spine at primary care clinics in 4 large healthcare systems who were eligible for osteoporosis screening and lacked indications of osteoporosis diagnoses or treatments in the prior year. We evaluated characteristics of participants with identified vertebral fractures that were associated with recognition of osteoporosis (diagnosis code in the health record; receipt of bone mineral density scans; and/or prescriptions for anti-osteoporotic medications). We used mixed models to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: A total of 114,005 participants (47% female; mean age 65 (interquartile range: 57-72) years) were evaluated. Of the 8579 (7%) participants with vertebral fractures identified, 3784 (44%) had recognition of osteoporosis within the subsequent year. In adjusted regressions, Black participants (OR (95% CI): 0.74 (0.57, 0.97)), younger participants (age 50-60: 0.48 (0.42, 0.54); age 61-64: 0.70 (0.60, 0.81)), and males (0.39 (0.35, 0.43)) were less likely to have recognized osteoporosis compared to white participants, adults aged 65 + years, or females. CONCLUSION: Individuals with identified vertebral fractures commonly did not have recognition of osteoporosis within a year, particularly those who were younger, Black, or male. Providers and healthcare systems should consider efforts to improve evaluation of osteoporosis in patients with vertebral fractures.

A pooled analysis of randomized, controlled, phase 3 trials investigating the efficacy and safety of a novel, fixed dose calcipotriene and betamethasone dipropionate cream for the topical treatment of plaque psoriasis.

BACKGROUND: Plaque psoriasis is a common, chronic and relapsing inflammatory skin disease clinically characterized by erythema and scaling desquamation. As over 90% of psoriasis patients benefit from topical therapies, local treatments continue to play an eminent role in management strategies. One such topical treatment is the fixed dose combination of calcipotriol (CAL) and betamethasone dipropionate (BDP). OBJECTIVES: Pooled analysis of two different phase 3 clinical trails to compare superiority regarding efficacy, safety and quality of life (QoL) between CAL/BDP PAD-cream and CAL/BDP TS. METHODS: The data from two phase 3, multicentre, randomized, investigator-blind, active and vehicle-controlled trials enrolling patients with psoriasis were pooled and analysed. Investigational products included a CAL/BDP cream based on PAD™ Technology (PAD-cream) designed for high skin penetration and increased patient preference, an active control (marketed CAL/BDP topical suspension/gel, in the following abbreviated as CAL/BDP TS) and cream vehicle, which were applied once daily for 8 weeks. RESULTS: Efficacy and safety of the novel CAL/BDP PAD-cream formulation for the topical treatment of psoriasis demonstrated superiority for all efficacy end points after 8 weeks of treatment. PGA treatment success for CAL/BDP PAD-cream (43.2%) was greater than CAL/BDP TS (31.9%; P < 0.0001), the mean per cent reduction in mPASI for CAL/BDP PAD-cream was 64.6% compared to 56.4% for CAL/BDP TS (P < 0.0001) and DLQI 0/1 was obtained by 43.8% in the CAL/BDP PAD-cream group versus 34.2% in the CAL/BDP TS group (P = 0.0005). There was no adverse drug reaction reported with a frequency of >1%, associated with the CAL/BDP PAD-cream. CONCLUSIONS: The novel fixed dose combination CAL/BDP PAD-cream offers greater efficacy, superior patient QoL and equivalent favourable safety for the topical treatment of psoriasis, in comparison to the currently available topical suspension/gel.

Ivermectin 1% cream for rosacea.

The etiology of papulopustular rosacea (PPR) is not well understood yet appears to involve both the innate and adaptive immune response in addition to possible infestation with Demodex mites. Current treatments for PPR consist mainly of antibiotics. Ivermectin cream 1%, a new topical treatment for PPR, possesses both anti-inflammatory and anti-parasitic properties. After 12 weeks of treatment, subjects treated with ivermectin cream 1% had significantly greater reductions in PPR symptoms and enhanced diseaserelated quality of life improvements compared to subjects who received vehicle. Furthermore, PPR symptoms continued to improve with prolonged treatment (40 weeks). Ivermectin cream 1% offers a multi-pronged approach to combat the complex pathophysiology of rosacea.

Level of asthma control and healthcare utilization in Latin America.

The purpose of this study was to investigate whether uncontrolled asthma was associated with healthcare outcomes among Latin American patients with asthma. We used data from 2168 patients with asthma who participated in the 2011 Latin America Asthma Insights and Management (AIM) survey. Using Global Initiative for Asthma (GINA) guidelines, patients were categorized as having asthma that was well-controlled, partly controlled, or uncontrolled. Overall, 7% of the patients surveyed had asthma that was classified as well-controlled. Patients whose asthma was not well-controlled were significantly more likely to report use of asthma medications (ORs ranging from 1.6-41) and to have had emergency healthcare visits or hospitalizations for their asthma in the previous year (ORs ranging from 2.1 to 5.9). They also reported decreases in their productivity compared to patients with well-controlled asthma. These associations suggest that emphasis on improving asthma control could have substantial effects on patient productivity and utilization of healthcare resources.

Systemic autoimmune disease mortality and occupational exposures.

OBJECTIVE: To generate hypotheses regarding occupational exposures that may cause systemic autoimmune diseases. METHODS: Based on examination of US death certificates, we identified deaths in 26 states for which a cause was listed as rheumatoid arthritis (RA) (n = 36,178), systemic lupus erythematosus (SLE) (n = 7,241), systemic sclerosis (n = 5,642), or other systemic autoimmune disease (n = 4,270). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to estimate associations between occupation and death from any systemic autoimmune disease, and from RA, SLE, and systemic sclerosis, specifically. Additionally, we estimated risks associated with occupational exposures, which were assigned using job-exposure matrices. RESULTS: A broad array of occupations was associated with death from systemic autoimmune diseases, including several of a priori interest. Farming occupation was associated with death from any systemic autoimmune disease (OR 1.3 [95% CI 1.2-1.4]), and increased risk was also seen with occupational exposure to animals and pesticides. Several industrial occupations were associated with death from any systemic autoimmune disease, including mining machine operators (OR 1.3 [95% CI 1.1-1.5]), miscellaneous textile machine operators (OR 1.2 [95% CI 1.0-1.4]), and hand painting, coating, and decorating occupations (OR 1.8 [95% CI 1.0-2.9]). These occupations were also significantly associated with death from the specific autoimmune diseases examined. Certain occupations entailing exposure to the public, such as teachers, were associated with systemic autoimmune disease-related death, whereas others, such as waiters and waitresses, were not. CONCLUSION: Our results suggest that death from systemic autoimmune diseases may be associated with occupational exposures encountered in farming and industry. The hypotheses generated in this study provide leads for future research on determinants of these diseases.

Compendium of chemical carcinogens by target organ: results of chronic bioassays in rats, mice, hamsters, dogs, and monkeys.

A compendium of carcinogenesis bioassay results organized by target organ is presented for 738 chemicals that are carcinogenic in chronic-exposure, long-term bioassays in at least 1 species. This compendium is based primarily on experiments in rats or mice; results in hamsters, monkeys, and dogs are also reported. The compendium can be used to identify chemicals that induce tumors at particular sites and to determine whether target sites are the same for chemicals positive in more than 1 species. The source of information is the Carcinogenic Potency Database (CPDB). which includes results of 6073 experiments on 1458 chemicals (positive or negative for carcinogenicity) that have been reported in Technical Reports of the National Cancer Institute/National Toxicology Program or in papers in the general published literature. The published CPDB includes detailed analyses of each test and citations. The CPDB is publicly available in several formats (http://potency.berkeley.edu). Chemical carcinogens are reported for 35 different target organs in rats or mice. Target organs in humans are also summarized for 82 agents that have been evaluated as human carcinogens at a particular target site by the International Agency for Research on Cancer (IARC). Comparisons are provided of target organs for mutagens versus nonmutagens and rats versus mice.

Paracelsus to parascience: the environmental cancer distraction.

Entering a new millennium seems a good time to challenge some old ideas, which in our view are implausible, have little supportive evidence, and might best be left behind. In this essay, we summarize a decade of work, raising four issues that involve toxicology, nutrition, public health, and government regulatory policy. (a) Paracelsus or parascience: the dose (trace) makes the poison. Half of all chemicals, whether natural or synthetic, are positive in high-dose rodent cancer tests. These results are unlikely to be relevant at the low doses of human exposure. (b) Even Rachel Carson was made of chemicals: natural vs. synthetic chemicals. Human exposure to naturally occurring rodent carcinogens is ubiquitous, and dwarfs the general public's exposure to synthetic rodent carcinogens. (c) Errors of omission: micronutrient inadequacy is genotoxic. The major causes of cancer (other than smoking) do not involve exogenous carcinogenic chemicals: dietary imbalances, hormonal factors, infection and inflammation, and genetic factors. Insufficiency of many micronutrients, which appears to mimic radiation, is a preventable source of DNA damage. (d) Damage by distraction: regulating low hypothetical risks. Putting huge amounts of money into minuscule hypothetical risks damages public health by diverting resources and distracting the public from major risks.

Supplement to the Carcinogenic Potency Database (CPDB): results of animal bioassays published in the general literature in 1993 to 1994 and by the National Toxicology Program in 1995 to 1996.

The Carcinogenic Potency Database (CPDB) is a systematic and unifying analysis of results of chronic, long-term cancer tests. This paper presents a supplemental plot of the CPDB, including 513 experiments on 157 test compounds published in the general literature in 1993 and 1994 and in Technical Reports of the National Toxicology Program in 1995 and 1996. The plot standardizes the experimental results (whether positive or negative for carcinogenicity), including qualitative data on strain, sex, route of compound administration, target organ, histopathology, and author's opinion and reference to the published paper, as well as quantitative data on carcinogenic potency, statistical significance, tumor incidence, dose-response curve shape, length of experiment, duration of dosing, and dose rate. A numerical description of carcinogenic potency, the TD(subscript)50(/subscript), is estimated for each set of tumor incidence data reported. When added to the data published earlier, the CPDB now includes results of 5,620 experiments on 1,372 chemicals that have been reported in 1,250 published papers and 414 National Cancer Institute/National Toxicology Program Technical Reports. The plot presented here includes detailed analyses of 25 chemicals tested in monkeys for up to 32 years by the National Cancer Institute. Half the rodent carcinogens that were tested in monkeys were not carcinogenic, despite usually strong evidence of carcinogenicity in rodents and/or humans. Our analysis of possible explanatory factors indicates that this result is due in part to the fact that the monkey studies lacked power to detect an effect compared to standard rodent bioassays. Factors that contributed to the lack of power are the small number of animals on test; a stop-exposure protocol for model rodent carcinogens; in a few cases, toxic doses that resulted in stoppage of dosing or termination of the experiment; and in a few cases, low doses administered to monkeys or early termination of the experiment even though the doses were not toxic. Among chemicals carcinogenic in both monkeys and rodents, there is some support for target site concordance, but it is primarily restricted to liver tumors. Potency values are highly correlated between rodents and monkeys. The plot in this paper can be used in conjunction with the earlier results published in the CRC Handbook of Carcinogenic Potency and Genotoxicity Databases [Gold LS, Zeiger E, eds. Boca Raton FL:CRC Press, 1997] and with our web site (http://potency.berkeley.edu), which includes a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency (TD50), and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Two summary tables permit easy access to the literature of animal cancer tests by target organ and by chemical. For readers using the CPDB extensively, a combined plot on diskette or other format is available from the first author. It includes all results published earlier and in this paper, ordered alphabetically by chemical. A SAS database is also available.

The causes and prevention of cancer: the role of environment.

The idea that synthetic chemicals such as DDT are major contributors to human cancer has been inspired, in part, by Rachel Carson's passionate book, Silent Spring. This chapter discusses evidence showing why this is not true. We also review research on the causes of cancer, and show why much cancer is preventable. Epidemiological evidence indicates several factors likely to have a major effect on reducing rates of cancer: reduction of smoking, increased consumption of fruits and vegetables, and control of infections. Other factors are avoidance of intense sun exposure, increases in physical activity, and reduction of alcohol consumption and possibly red meat. Already, risks of many forms of cancer can be reduced and the potential for further reductions is great. If lung cancer (which is primarily due to smoking) is excluded, cancer death rates are decreasing in the United States for all other cancers combined. Pollution appears to account for less than 1% of human cancer; yet public concern and resource allocation for chemical pollution are very high, in good part because of the use of animal cancer tests in cancer risk assessment. Animal cancer tests, which are done at the maximum tolerated dose (MTD), are being misinterpreted to mean that low doses of synthetic chemicals and industrial pollutants are relevant to human cancer. About half of the chemicals tested, whether synthetic or natural, are carcinogenic to rodents at these high doses. A plausible explanation for the high frequency of positive results is that testing at the MTD frequently can cause chronic cell killing and consequent cell replacement, a risk factor for cancer that can be limited to high doses. Ignoring this greatly exaggerates risks. Scientists must determine mechanisms of carcinogenesis for each substance and revise acceptable dose levels as understanding advances. The vast bulk of chemicals ingested by humans is natural. For example, 99.99% of the pesticides we eat are naturally present in plants to ward off insects and other predators. Half of these natural pesticides tested at the MTD are rodent carcinogens. Reducing exposure to the 0.01% that are synthetic will not reduce cancer rates. On the contrary, although fruits and vegetables contain a wide variety of naturally-occurring chemicals that are rodent carcinogens, inadequate consumption of fruits and vegetables doubles the human cancer risk for most types of cancer. Making them more expensive by reducing synthetic pesticide use will increase cancer. Humans also ingest large numbers of natural chemicals from cooking food. Over a thousand chemicals have been reported in roasted coffee: more than half of those tested (19/28) are rodent carcinogens. There are more rodent carcinogens in a single cup of coffee than potentially carcinogenic pesticide residues in the average American diet in a year, and there are still a thousand chemicals left to test in roasted coffee. This does not mean that coffee is dangerous but rather that animal cancer tests and worst-case risk assessment, build in enormous safety factors and should not be considered true risks. The reason humans can eat the tremendous variety of natural chemical "rodent carcinogens" is that humans, like other animals, are extremely well protected by many general defense enzymes, most of which are inducible (i.e., whenever a defense enzyme is in use, more of it is made). Since the defense enzymes are equally effective against natural and synthetic chemicals one does not expect, nor does one find, a general difference between synthetic and natural chemicals in ability to cause cancer in high-dose rodent tests. The idea that there is an epidemic of human cancer caused by synthetic industrial chemicals is false. In addition, there is a steady rise in life expectancy in the developed countries. Linear extrapolation from the maximum tolerated dose in rodents to low level exposure in humans has led to grossly exaggerated mortality forecasts. Such extrapo

The prevention of cancer.

1. The major causes of cancer are as follows: (a) Smoking: about a third of U.S. cancer (90% of lung cancer). (b) Dietary imbalances, e.g., lack of dietary fruits and vegetables: The quarter of the population eating the least fruits and vegetables has double the cancer rate for most types of cancer compared to the quarter eating the most; micronutrients may account for much of the protective effect of fruits and vegetables. Excess calories may also contribute to cancer. (c) Chronic infections: mostly in developing countries. (d) Hormonal factors influenced by life-style. 2. There is no epidemic of cancer, except for lung cancer due to smoking. Cancer mortality rates have declined 16% since 1950 (excluding lung cancer and adjusted for the increased life span of the population). 3. Regulatory policy that is focused on traces of synthetic chemicals is based on misconceptions about animal cancer tests. Recent research contradicts these ideas: (a) Rodent carcinogens are not rare. Half of all chemicals tested in standard high-dose animal cancer tests, whether occurring naturally or produced synthetically, are "carcinogens." (b) There are high-dose effects in these rodent cancer tests that are not relevant to low-dose human exposures and which can explain the high proportion of carcinogens. (c) Though 99.9% of the chemicals humans ingest are natural, the focus of regulatory policy is on synthetic chemicals. Over 1000 chemicals have been described in coffee: 27 have been tested and 19 are rodent carcinogens. Plants that we eat contain thousands of natural pesticides which protect plants from insects and other predators: 64 have been tested and 35 are rodent carcinogens. 4. There is no convincing evidence that synthetic chemical pollutants are important for human cancer. Regulations that try to eliminate minuscule levels of synthetic chemicals are enormously expensive: EPA estimates that total expenditures on environmental regulations cost $140 billion/year. It has been estimated by others that the United States spends 100 times more to prevent one hypothetical, highly uncertain death from a synthetic chemical than it spends to save a life by medical intervention. Attempting to reduce tiny hypothetical risks also has costs; for example, if reducing synthetic pesticides makes fruits and vegetables more expensive, thereby decreasing consumption, then cancer will be increased. 5. Improved health will come from knowledge due to biomedical research and from life-style changes by individuals. Little money is spent on biomedical research or on educating the public about lifestyle hazards, compared to the cost of regulations.

What do animal cancer tests tell us about human cancer risk?: Overview of analyses of the carcinogenic potency database.

Many important issues in carcinogenesis can be addressed using our Carcinogenic Potency Database, which analyzes and standardizes the literature of chronic carcinogenicity tests in laboratory animals. This review is an update and overview of our analyses during the past 15 years, using the current database that includes results of 5152 experiments on 1298 chemicals. We address the following: 1. More than half the 1298 chemicals tested in long-term experiments have been evaluated as carcinogens. We describe this positivity rate for several subsets of the data (including naturally occurring and synthetic chemicals), and we hypothesize and important role in the interpretation of results for increased cell division due to administration of high doses. 2. Methodological issues in the interpretation of animal cancer tests: constraints on the estimation of carcinogenic potency and validity problems associated with using the limited data from bioassays to estimate human risk, reproducibility of results in carcinogenesis bioassays, comparison of lifetable and summary methods of analysis, and summarizing carcinogenic potency when multiple experiments on a chemical are positive. 3. Positivity is compared in bioassays for two closely related species, rats and mice, tested under similar experimental conditions. We assess what information such a comparison can provide about interspecies extrapolation. 4. Rodent carcinogens induce tumors in 35 different target organs. We describe the frequency of chemicals that induce tumors in rats or mice at each target site, and we compare target sites of mutagenic and nonmutagenic rodent carcinogens. 5. A broad perspective on evaluation of possible cancer hazards from rodent carcinogens is given, by ranking 74 human exposures (natural and synthetic) on the HERP indes.

Environmental pollution, pesticides, and the prevention of cancer: misconceptions.

The major causes of cancer are: 1) smoking, which accounts for about a third of U.S. cancer and 90% of lung cancer; 2) dietary imbalances: lack of sufficient amounts of dietary fruits and vegetables. The quarter of the population eating the fewest fruits and vegetables has double the cancer rate for most types of cancer than the quarter eating the most; 3) chronic infections, mostly in developing countries; and 4) hormonal factors, influenced primarily by lifestyle. There is no cancer epidemic except for cancer of the lung due to smoking. Cancer mortality rates have declined by 16% since 1950 (excluding lung cancer). Regulatory policy that focuses on traces of synthetic chemicals is based on misconceptions about animal cancer tests. Recent research indicates that rodent carcinogens are not rare. Half of all chemicals tested in standard high-dose animal cancer tests, whether occurring naturally or produced synthetically, are "carcinogens"; there are high-dose effects in rodent cancer tests that are not relevant to low-dose human exposures and which contribute to the high proportion of chemicals that test positive. The focus of regulatory policy is on synthetic chemicals, although 99.9% of the chemicals humans ingest are natural. More than 1000 chemicals have been described in coffee: 28 have been tested and 19 are rodent carcinogens. Plants in the human diet contain thousands of natural "pesticides" produced by plants to protect themselves from insects and other predators: 63 have been tested and 35 are rodent carcinogens. There is no convincing evidence that synthetic chemical pollutants are important as a cause of human cancer. Regulations targeted to eliminate minuscule levels of synthetic chemicals are enormously expensive: the Environmental Protection Agency has estimated that environmental regulations cost society $140 billion/year. Others have estimated that the median toxic control program costs 146 times more per hypothetical life-year saved than the median medical intervention. Attempting to reduce tiny hypothetical risks has other costs as well: if reducing synthetic pesticides makes fruits and vegetables more expensive, thereby decreasing consumption, then the cancer rate will increase, especially for the poor. The prevention of cancer will come from knowledge obtained from biomedical research, education of the public, and lifestyle changes made by individuals. A reexamination of priorities in cancer prevention, both public and private, seems called for.

The causes and prevention of cancer: gaining perspective.

Epidemiological studies have identified several factors that are likely to have a major effect on reducing rates of cancer: reduction of smoking, increased consumption of fruits and vegetables, and control of infections. Other factors include avoidance of intense sun exposure, increased physical activity, and reduced consumption of alcohol and possibly red meat. Risks of many types of cancer can already be reduced, and the potential for further reductions is great. In the United States, cancer death rates for all cancers combined are decreasing, if lung cancer (90% of which is due to smoking), is excluded from the analysis. We review the research on causes of cancer and show why much cancer is preventable. The idea that traces of synthetic chemicals, such as DDT, are major contributors to human cancer is not supported by the evidence, yet public concern and resource allocation for reduction of chemical pollution are very high, in part because standard risk assessment uses linear extrapolation from limited data in high-dose animal cancer tests. These tests are done at the maximum tolerated dose (MTD) and are typically misinterpreted to mean that low doses of synthetic chemicals and industrial pollutants are relevant to human cancer. About half the chemicals tested, whether synthetic or natural, are carcinogenic to rodents at such high doses. Almost all chemicals in the human diet are natural. For example, 99.99% of the pesticides we eat are naturally present in plants to ward off insects and other predators. Half of the natural pesticides that have been tested at the MTD are rodent carcinogens. Cooking food produces large numbers of natural dietary chemicals. Roasted coffee, for example, contains more than 1000 chemicals: of 27 tested, 19 are rodent carcinogens. Increasing evidence supports the idea that the high frequency of positive results in rodent bioassays is due to testing at the MTD, which frequently can cause chronic cell killing and consequent cell replacement-a risk factor for cancer that can be limited to high doses. Because default risk assessments use linear extrapolation, which ignores effects of the high dose itself, low-dose risks are often exaggerated.

Trichloroethylene cancer risk: simplified calculation of PBPK-based MCLs for cytotoxic end points.

Cancer risk assessments for trichloroethylene (TCE) based on linear extrapolation from bioassay results are questionable in light of new data on TCE's likely mechanism of action involving induced cytotoxicity, for which a threshold-type dose-response model may be more appropriate. Previous studies have shown that if a genotoxic mechanism for TCE is assumed, algebraic methods can considerably simplify the use of physiologically based pharmacokinetic (PBPK) models to estimate virtually safe environmental concentrations for humans based on rodent cancer-bioassay data. We show here how such methods can be extended to the case in which TCE is assumed to induce cancer via cytotoxicity, to estimate environmentally safe concentrations based on rodent toxicity data. These methods can be substituted for the numerical methods typically used to calculate PBPK-effective doses when these are defined as peak concentrations. We selected liver and kidney as plausible target tissues, based on an analysis of rodent TCE-bioassay data and on a review of related data bearing on mechanism. Tumor patterns in rodent bioassays are shown to be consistent with our estimates of PBPK-based, effective cytotoxic doses to mice and rats used in these studies. When used with a margin of exposure of 1000, our method yielded maximum concentration levels for TCE of 16 ppb (87 micrograms/m3) for TCE in air respired 24 hr/day, 700 ppb (3.8 mg/m3) for TCE in air respired for relatively brief daily periods (e.g., 0.5 hr while showering/bathing), and 210 micrograms/liter for TCE in drinking water assuming a daily 2-liter ingestion. Cytotoxic effective doses were also estimated for occupational respiratory exposures. These estimates indicate that the current OSHA permissible exposure limit for TCE would produce metabolite concentrations that exceed an acute no observed adverse effect level for hepatotoxicity in mice. On this basis, the OSHA TCE limit is not expected to be protective.

Concordance between rats and mice in bioassays for carcinogenesis.

According to current policy, chemicals are evaluated for possible cancer risk to humans at low dose by testing in bioassays in which high doses of the chemical are given to rodents. Thus, risk is extrapolated from high dose in rodents to low dose in humans. The accuracy of these extrapolations is generally unverifiable because data on humans are limited. However, it is feasible to examine the accuracy of extrapolations from mice to rats. If mice and rats are similar with respect to carcinogenesis, this provides some evidence in favor of interspecies extrapolations; conversely, if mice and rats are different, this casts doubt on the validity of extrapolations from mice to humans. One measure of interspecies agreement is concordance, the percentage of chemicals that are classified the same way as to carcinogenicity in mice and rats. Observed concordance in National Cancer Institute/National Toxicology Program bioassays is about 75%, which may seem on the low side because mice and rats are closely related species tested under the same experimental conditions. However, observed concordance could underestimate true concordance due to measurement error in the bioassays-a possibility demonstrated by Piegorsch et al. (Risk Anal. 12, 115-121, 1992). Expanding on this work, we show that the bias in observed concordance can be either positive or negative: an observed concordance of 75% can arise if the true concordance is anything between 20 and 100%. In particular, observed concordance can seriously overestimate true concordance.