Search

Over the years, some activist groups have targeted cosmetics as possible human health threats, claiming that cosmetic ingredients are not adequately tested for safety and may pose risks to consumers. The groups allege that industry practices related to safety testing are flawed, that there is little government oversight, and that cosmetics contain cancer-causing chemicals and other toxicants. A critical review of the scientific data related to these claims indicates the following: (1) Industry has the primary responsibility to ensure that all ingredients, preservatives, and coformulants used in products are safe for their intended uses. (2) The U.S. Food and Drug Administration (FDA) has regulatory oversight of the cosmetic industry. Its authority includes the banning or restriction of ingredients for safety reasons. (3) The Cosmetic Ingredient Review (CIR), an independent, scientific review board, critically evaluates chemical ingredients used in cosmetics and publishes the results of its findings in the peer-reviewed literature. (4) Health-related allegations about cosmetic ingredients are generally based on the results of high-dose laboratory testing in animals and have little relevance for humans. As true now as when Paracelsus said it in the 16th century, “It is the dose that makes the poison.” (5) The health-related allegations involving specific chemicals (e.g., phthalates, parabens, and 1,3-butadiene) fail to consider important scientific studies and recent regulatory conclusions about these chemicals, which have found that they are not hazardous. (6) Animal and human physiology differ in crucial ways, further invalidating simplistic attempts to extrapolate rodent testing to human health risks. The cosmetic industry should be encouraged to publish more of its toxicity studies and safety evaluations, which would aid in dispelling the uncertainty that some consumers have about cosmetic safety. [ABSTRACT FROM AUTHOR]

Until recently, the published literature on inhalation studies with laboratory animals and cigarette smoke consisted entirely of negative findings, as far as neoplastic disease is concerned. This paper brings readers up to date, with analyses of recent studies that do indeed appear to report success after so many years of failure. The paper consists of a brief analysis of the literature up until a couple of years ago, giving brief, representative examples of inhalation studies with the five main species of laboratory animals that have been used: rat, mouse, hamster, dog, and nonhuman primate. A brief examination of the various technologies used to expose laboratory animals is given, along with an analysis of the histopathology and related toxicology data (specifically, biomarkers of exposure) that have been reported. The paper concludes by briefly mentioning the most recent studies, where positive results have been reported. [ABSTRACT FROM AUTHOR]

Although Urea is officially described as a buffering agent, humectant. and skin-conditioning agent-humectant for use in cosmetic products, there is a report stating that Urea also is used in cosmetics for its desquamating and antimicrobial action. In 2001, the Food and Drug Administration (FDA) reported that Urea was used in 239 formulations. Concentrations of use for Urea ranged from 0.01% to 10%. Urea is generally recognized as safe by FDA for the following uses: side-seam cements for food contact; an inhibitor or stabilizer in pesticide formulations and formulations applied to animals: internal sizing for paper and paperboard and surface sizing and coating of paper and paper board that contact water-in-oil dairy emulsions, low-moisture fats and oils, moist bakery products, dry solids with surface containing no free fats or oil, and dry solids with the surface of fat or oil; and to facilitate fermentation of wine. Urea is the end product of mammalian protein metabolism and the chief nitrogenous compound of urine. Urea concentrations in muscle, liver, and fetuses of rats increased after a subcutaneous injection of Urea. Urea diffused readily through the placenta and into other maternal and fetal organs. The half-life of Urea injected into rabbits was on the order of several hours, and the reutilization rate was 32.2% to 88.8%. Urea given to rats by a bolus injection or continuous infusion resulted in distribution to the following brain regions: frontal lobe, caudate nucleus, hippocampus, thalamus plus hypothalamus, pons and white matter (corpus callosum). The permeability constant after treatment with Urea of whole skin and the dermis of rabbits was 2.37 ± 0.13 (x106) and 1.20 ± 0.09 (x10³) cm/min, respectively. The absorption of Urea across normal and abraded human skin was 9.5% ± 2.3% and 67.9% ± 5.6%, respectively. Urea increased the skin penetration of other compounds, including hydrocortisone. No toxicity was observed for Urea at levels as high as 2000 mg/kg in acute oral studies using female rats or mice. No signs of toxicity were observed in male piglets dosed orally with up to 4 g/kg Urea for 5 days. Dogs dosed orally with 5 to 30 g/L Urea for 4 to 10 days had signs of toxicity. including weakness, anorexia, vomiting and retching, diarrhea and a decreased body temperature, which led to a deep torpor or coma. No significant microscopic changes were observed in the skin of male nude mice dermally exposed to 100% Urea for 24 b. No observable effect on fetal development was seen in rats and mice dosed orally with an aqueous solution of Urea (2000 mg/kg) on days 10 and 12 of gestation. The mean number of implants, live fetuses, percent fetal resorptions, mean fetal weight, and percent fetuses malformed were comparable to control group. A detergent containing 15% Urea was injected into pregnant ICR-JCI mice and dams and fetuses had no significant differences when compared to control animals. Urea given orally did not enhance the developmental toxicity of N-nitrosomethylurea. Female Sprague-Dawley rats injected in the uterine born with 0.05 ml Urea on day 3 (preimplantation) or on day 7 (post implantation) exhibited no maternal mortality or morbidity; a dose-dependent reduction in embryo survival was seen with preimplantation treatment. Urea injected intra-amniotically induces mid-trimester abortions in humans. Urea was not genotoxic in several bacterial and mammalian assays; although in assays where Urea was used at a bigb concentration, genotoxicity was found, many in in vitro assays. Urea is commonly used in studies of DNA because it causes uncoiling of DNA molecules. Urea was not carcinogenic in Fisher 344 rats or C57B1/6 mice fed diets containing up to 4.5% Urea. Exposure of normal human skin to 60% Urea produced no significant irritation in one study, but 5% Urea was slightly irritating and 20% Urea was irritating in other reports. Burning sensations are the most frequently reported effect of Urea used alone or with other agents in treatment of diseased skin. Overall, there are few reports of sensitization among the many clinical studies that report use of Urea in treatment of diseased skin. The Cosmetic Ingredient Review (CIR) Expert Panel determined the data provided in this report to be sufficient to assess the safety of Urea. The Panel did note that Urea can cause uncoiling of DNA, a property used in many DNA studies, but concluded that this in vitro activity is not linked to any in vivo genotoxic activity. Although noting that formulators should be aware that Urea can increase the percutaneous absorption of other chemicals, the CIR Expert Panel concluded that Urea is safe as used in cosmetic products. [ABSTRACT FROM AUTHOR]

Results from carcinogenicity studies are generally not available for drugs until the time of approval. Many people, including healthy volunteers are often exposed to pharmacologically active doses of the drug before carcinogenicity results are available. The Food and Drug Administration (FDA) Center for Drug Evaluation and Research uses results of genetic toxicology studies as a surrogate for carcinogenicity during the drug development phase (clinical trials). A number of issues are considered in deciding whether drugs that give positive results in genetic toxicology studies can be given to subjects in clinical trials. These relate to the drug indication, the target population, duration of treatment, and importance of the drug. In general, single-dose clinical studies are permitted regardless of the genetox results. In situations where a genetic toxicology assay showed a positive result, some review divisions have asked sponsors to perform a Syrian hamster embryo (SHE) cell transformation assay or a p53 carcinogenicity study prior to allowing repeat-dose clinical trials to proceed. This paper discusses alternatives to SHE cell and p53 assays when faced with a positive result in a genetic toxicology assay. In addition, this paper discusses factors to consider when setting limits for genotoxic impurities in drug substances and products. [ABSTRACT FROM AUTHOR]

Anthraquinone (AQ) (9,10-anthracenedione) is an important compound in commerce. Many structurally related AQ derivatives are medicinal natural plant products. Examples include 1-hydroxyanthraquinone (1-OH-AQ) and 2-hydroxyanthraquinone (2-OH-AQ), which are also metabolites of AQ. Some commercial AQ is produced by the oxidation of anthracene (AQ-OX). In the recent past, the anthracene used was distilled from coal tar and different lots of derived AQ often contained polycyclic aromatic hydrocarbon contaminants, particularly 9-nitroanthracene (9-NA). Many toxicology studies on AQ used contaminated anthracene-derived AQ-OX, including a National Toxicology Program (NTP) 2-year cancer bioassay that reported a weak to modest increase in tumors in the kidney and bladder of male and female F344/N rats and in the livers of male and female B6C3F1mice. The AQ-OX used in that bioassay was mutagenic and contained 9-NA and other contaminants. In contrast, purified AQ is not genotoxic. The purpose of this paper is to provide additional information to help iterpret the NTP cancer bioassay. This paper describes a quantitative analytical study of the NTP anthracene-derived AQ-OX test material, and presents the results of mutagenicity studies with the 1-OH-AQ and 2-OH-AQ metabolites and the primary contaminant 9-NA. Purified 1-OH-AQ and 2-OH-AQ exhibited only weak mutagenic activity in selected strains of tester bacteria and required S9. Literature reports of potent mutagenic activity for 1-OH-AQ and 2-OH-AQ in bacteria minus S9 are, once again, very likely the result of the presence of contaminants in the test samples. Weak activity and limited production of the 1-OH-AQ and 2-OH-AQ metabolites are possible reasons that AQ fails to exhibit activity in numerous genotoxicity assays. 9-NA was mutagenic in tester strains TA98 and TA100 minus S9. This pattern of activity is consistent with that seen with the contaminated AQ-OX used in the NTP bioassay. Analysis of all the mutagenicity and analytical data, however, indicates that the mutagenic contamination in the NTP bioassay probably resides with compounds in addition to 9-NA. 9-NA exhibited potent mutagenic activity in the L5178Y mammalian cell mutagenicity assay in the presence of S9. The positive response was primarily associated with an increase in small colony mutants suggesting a predominance of a clastogenic mechanism. Quantitative mutagenicity and carcinogenicity potency estimates indicate that it is plausible that the contaminants alone in the NTP AQ-OX bioassay could have been responsible for all of the observed carcinogenic activity. Although AQ-OX is no longer commercially used in the United States, many of the reported genotoxicity and carcinogenicity results in the literature for AQ and AQ derivative compounds must be viewed with caution. [ABSTRACT FROM AUTHOR]

In this paper, carcinogenicity classifications of the chlorinated solvent trichloroethylene (TCE) made by the European Union Commission Expert Groups in 1976, 1988, and 2001 are scrutinized and alternative classifications are proposed. It is argued that the TCE database at these three points in time could have been interpreted to fulfill the criteria for stricter classifications than those actually made. Implications of this for the classification process are discussed. [ABSTRACT FROM AUTHOR]

In this paper a semianalytical model has been proposed to predict the rate at which oil components dissolve in water when an oil spill occurs in a marine environment. The model breaks the oil into a number of pseudocomponents proportional to the number of compounds originally present in the oil and calculates the rate of dissolution for each component. In addition, the components are divided into paraffinic, naphthenic, and aromatic hydrocarbon types and the amount of dissolution of each pseudocomponent is calculated versus time. In this method the concentration of most toxic components of oil (mainly monoaromatics) is determined. The model considers variable surface area and slick thickness and requires oil specifications (i.e., American Petroleum Institute [API] gravity and boiling point) in addition to air and water temperatures and speeds. The model has been applied to a Kuwaiti crude oil and its products naphtha and kerosene samples at 20°C and 40°C. The results could be useful in selection of an appropriate method for oil spill clean up as well as simulation of environmental impact of oil spill from toxicity points of view. [ABSTRACT FROM AUTHOR]

An evaluation of the scientific literature for trichloroethylene (TCE) identified two reports of ocular defects, specifically microphthalmia/anophthalmia, following prenatal TCE exposure in rats. Herein, these reports are analyzed in detail and interpreted within the context of other developmental TCE exposure studies. The ocular findings following prenatal TCE exposure are reported in studies that were not designed specifically for developmental safety assessment, and thus did not use standard experimental practices. Furthermore, these findings most commonly occurred at TCE doses associated with considerable maternal toxicity. Among the 18 published studies using developmental TCE exposures, only 3 used doses sufficiently high enough to result in maternal toxicity, and of these, only the 2 discussed in detail in this paper demonstrated ocular defects in the offspring. Furthermore, statistically significant effects were only observed at doses that were above the currently accepted guideline limit dose of 1000 mg/kg body weight. All other TCE developmental exposure studies failed to demonstrate ocular defects as a result of prenatal exposure. These results suggest that the micro-/anophthalmia findings were likely a consequence of delivery of an extremely high bolus TCE dose that is irrelevant to human environmental exposure scenarios. [ABSTRACT FROM AUTHOR]

This paper reports the toxicity and environmental impact of neutralents produced from the hydrolysis of binary chemical agent precursor chemicals DF (methylphosphonic difluoride) and QL (2-[bis(1-methylethyl)amino]ethyl ethyl methylphosphonite). Following a literature review of the neutralent mixtures and constituents, basic toxicity tests were conducted to fill data gaps, including acute oral and dermal median lethal dose assays, the Ames mutagenicity test, and ecotoxicity tests. For methylphosphonic acid (MPA), a major constituent of DF neutralent, the acute oral LD50 in the Sprague-Dawley rat was measured at 1888 mg/kg, and the Ames test using typical tester strains of Salmonella typhimurium and Escherichia coli was negative. The 48-h LC50 values for pH-adjusted DF neutralent with Daphnia magna and Cyprinodon variegatus were > 2500 mg/L and 1593 mg/L, respectively. The acute oral LD50 values in the rat for QL neutralent constituents methylphosphinic acid (MP) and 2-diisopropylaminoethanol (KB) were both determined to be 940 mg/kg, and the Ames test was negative for both. Good Laboratory Practice (GLP)-compliant ecotoxicity tests for MP and KB gave 48-h D. magna EC50 values of 6.8 mg/L and 83 mg/L, respectively. GLP-compliant 96-h C. variegatus assays on MP and KB gave LC50 values of 73 and 252 mg/L, respectively, and NOEC values of 22 and 108 mg/L. QL neutralent LD50 values for acute oral and dermal toxicity tests were both > 5000 mg/kg, and the 48-h LD50 values for D. magna and C. variegatus were 249 and 2500 mg/L, respectively. Using these data, the overall toxicity of the neutralents was assessed. [ABSTRACT FROM AUTHOR]

A number of genetically modified (GM) crops bioengineered to express agronomic traits including herbicide resistance and insect tolerance have been commercialized. Safety studies conducted for the whole grains and food and feed fractions obtained from GM crops (i.e., bioengineered foods) bear similarities to and distinctive differences from those applied to substances intentionally added to foods (e.g., food ingredients). Similarities are apparent in common animal models, route of exposure, duration, and response variables typically assessed in toxicology studies. However, because of differences in the nutritional and physical properties of food ingredients and bioengineered foods and in the fundamental goals of the overall safety assessment strategies for these different classes of substances, there are recognizable differences in the individual components of the safety assessment process. The fundamental strategic difference is that the process for food ingredients is structured toward quantitative risk assessment whereas that for bioengineered foods is structured for the purpose of qualitative risk assessment. The strategy for safety assessment of bioengineered foods focuses on evaluating the safety of the transgenic proteins used to impart the desired trait or traits and to demonstrate compositional similarity between the grains of GM and non-GM comparator crops using analytical chemistry and, in some cases, feeding studies. Despite these differences, the similarities in the design of safety studies conducted with bioengineered foods should be recognized by toxicologists. The current paper reviews the basic principles of safety assessment for bioengineered foods and compares them with the testing strategies applied to typical food ingredients. From this comparison it can be seen that the strategies used to assess the safety of bioengineered foods are at least as robust as that used to assess the safety of typical food ingredients. [ABSTRACT FROM AUTHOR]

The process of toxicological analysis of postmortem specimens can reveal some special difficulty compared to the clinically derived specimens. Many drugs are not stable and the chemical changes that occur in the specimens, due to the hydrolysis processing, the time passed, the drug metabolism, and matrix effect, even when the postmortem interval is short, may affect the interpretation of the toxicological results. This interpretation may be critical, not only to the thorough investigation of different kind of forensic cases, but also to clinical or other cases as it provides very significant challenges to the scientists. This article reviews (a) particular toxicological issues associated with some toxic substances responsible for common lethal or nonlethal poisonings, such as opiates, cannabis, and cocaine and the vast number of factors that affect drug concentration; and (b) focuses on toxicological issues associated with the analytical findings of certain postmortem specimens. The toxic substances cited in the present paper are the most commonly found in forensic cases in Greece. The investigation of these drug-related deaths has revealed that heroin, alone or in combination with other psychoactive substances, such as cannabis and cocaine, is the main drug involved in these deaths. [ABSTRACT FROM AUTHOR]

An oral dose of 1000 mg/kg body weight/day is mentioned in Organisation for Economic Cooperation and Development (OECD) and European Union (EU) guidelines as a default maximum dose in limit tests for studies on reproductive toxicity. This paper investigated whether upper range human exposure data from the workplace are supportive of this limit dose as an upper limit of possible human exposure. To this end, published exposure data as well as data from the database MEGA of the German "Berufsgenossenschaften" were evaluated. These data indicate that exposure concentrations in the range of 500 to 2000 mg/m3 (time-weighted averages) can be considered high human exposures to volatile compounds. Inhalation exposure to aerosols and dermal exposure result in lower dose levels. By applying suitable extrapolation factors, it was concluded that occupational exposures up to 325 mg/m3 can reliably be assessed with limit tests using a dose level of 1000 mg/kg/day. The limit dose has been proposed for use in the EU as a starting point to derive specific concentration limits for hazard classification of preparations containing reproductive toxicants, with the objective to consider the potency of the substances. This analysis shows that for some groups of chemicals, instead of the limit dose, the putative maximum levels of human exposure should be taken into account when deriving concentration limits for the classification of preparations. Furthermore, possible deviations from a linear correlation between concentration in the preparation and exposure should be considered. [ABSTRACT FROM AUTHOR]

The biological activities of fullerene derivatives have attracted much attention in the last decade. In this paper, effects of dimalonic acid C60 (DMA C60) on cytoplasmic membrane, intracellular calcium concentration ([Ca2+]i), and mitochondrial membrane in HeLa cells were studied by using laser scanning confocal microscopy together with fluorescent probes propidium iodide (PI), fluo-3 acetoxymethyl ester (fluo-3 AM), and tetramethyl rhodamine methyl ester (TMRM). The data showed that under laser irradiation produced by a Kr/Ar laser source with a low power less than 1 mW, DMA C60 might induce damages against both cytoplasmic and mitochondrial membranes in a time- and dose-dependent manner. Prior to leakage of cytoplasmic membrane, a transient increase in [Ca2 +]i occurred due to influx of calcium from the culture medium. These data provided some novel clues to explain the mechanisms involved in the photo-induced cytotoxicity of fullerene derivatives. [ABSTRACT FROM AUTHOR]

Pharmacogenetics is the study of genetic variations that cause a variable drug response characterized by alteration in drug metabolism or in pharmacodynamics. The polymorphisms in genes encoding receptors relevant to treatment cause variation in sensitivity to many drugs. β2 Adrenoceptor genetic variation contributes to regulation of blood pressure and hemodynamic changes by mediating peripheral vasodilatation. Laryngoscopy and tracheal intubation associated with hemodynamic changes. Although there are four nonsynomic single-nucleotide polymorphisms (SNPs) of β2 adrenoceptor gene, codon 16 (Arg16Gly) and codon 27 (Gln27Glu) SNPs are both common and functionally important. In this paper, the authors investigated the β2 adrenoceptor Gly16 and Glu27 SNPs in response to drugs relevant to anesthesia and how these SNPs impacted upon the cardiovascular phenotypes. The authors measured arterial systolic and diastolic blood pressure, heart rate, and rate-pressure product before induction of anesthesia and 1 min following laryngoscopy and tracheal intubation. Genomic DNA was amplified and genotyped using allele-specific polymerase chain reaction (ASPCR) and restriction fragment length polymorphism (RFLP) assays, respectively. When the authors compared hemodynamic results according to genotypes, the patients with Gln homozygote allele at codon 27 exhibited significant increase of heart rate than patients with Glu allele after laryngoscope and tracheal intubation. [ABSTRACT FROM AUTHOR]

With the fast development of nanotechnology, the nanomaterials start to cause people's attention for potential toxic effect. In this paper, the cytotoxicity and oxidative stress caused by 20-nm cerium oxide (CeO2) nanoparticles in cultured human lung cancer cells was investigated. The sulforhodamine B method was employed to assess cell viability after exposure to 3.5, 10.5, and 23.3 μg/ml of CeO2 nanoparticles for 24, 48, and 72 h. Cell viability decreased significantly as a function of nanoparticle dose and exposure time. Indicators of oxidative stress and cytotoxicity, including total reactive oxygen species, glutathione, malondialdehyde, α-tocopherol, and lactate dehydrogenase, were quantitatively assessed. It is concluded from the results that free radicals generated by exposure to 3.5 to 23.3 μg/ml CeO2 nanoparticles produce significant oxidative stress in the cells, as reflected by reduced glutathione and α-tocopherol levels; the toxic effects of CeO2 nanoparticles are dose dependent and time dependent; elevated oxidative stress increases the production of malondialdehyde and lactate dehydrogenase, which are indicators of lipid peroxidation and cell membrane damage, respectively. [ABSTRACT FROM AUTHOR]

The number of available dietary supplements containing “starch blockers” intended for weight loss has risen dramatically in recent years. These supplements are believed to reduce carbo- hydrate-derived calories by interfering with α-amylase, the digestive enzyme responsible for conversion of complex carbohydrates to simple absorbable sugars. The present paper reports the findings of single- and multiple-dose (4-week) oral toxicity studies in rats of the marketed dietary supplement Blockal. Blockal contains as its main ingredient Phase 2 Starch Neutralizer (Phase 2 or Phaseolamin 2250), a standardized extract derived from the common white kidney bean ( Phaseolus vulgaris ) that has been shown to have α-amylase-inhibiting activity. The Blockal acute oral LD 50 exceeded the highest dose tested (3 g/kg body weight [bw]), which provided a single dose of 1668 mg/kg bw of Phase 2 white kidney bean extract. The no-observed-effect level (NOEL) seen in the 4-week study was equivalent to the highest Blockal dose tested (2 g/kg bw/day), which provided 1112 mg/kg/day of Phase 2 white kidney bean extract. The results of these studies support and are consistent with the safety of the marketed dietary supplement Blockal, and indirectly, the safety of its main ingredient, Phase 2 Starch Neutralizer (Phase 2 or Phaseolamin 2250), a standardized extract derived from the common white kidney bean. [ABSTRACT FROM AUTHOR]

Computer modeling of aggregate exposure provides the capability to estimate the range of doses that can occur from product use and to understand the relative importance of different routes of exposure. This paper presents an assessment of aggregate occupational exposure to two glycol ethers used as solvents in floor maintenance products for industrial and institutional facilities, using a simulation tool named PROMISE. Three commercial floor-care products were assumed to be applied in sequence—a floor stripper, then a floor cleaner, and lastly a protective coating. The glycol ethers modeled were ethylene glycol butyl ether (EGBE) in the floor stripper and in the floor cleaner, and dipropylene glycol methyl ether (DPGME) in the coating. Modeling uncertainty was assessed through a comparison of the PROMISE inhalation exposure estimates with those from an independent model (MCCEM), and parameter uncertainty was investigated using PROMISE software's Monte Carlo simulation capabilities. Modeling results indicated that inhalation is the dominant exposure route. The predicted average air concentration and inhalation dose from PROMISE agreed with the second model (MCCEM) within 10%. Monte Carlo simulation indicated that the upper end of the aggregate-dose distribution for the scenario was more than 50% higher than the value of the point estimate. The modeled 8-h TWA concentrations for EGBE and DPGME were lower than the corresponding permissible exposure limits American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values (TLV) by at least a factor of 20, indicating that under the assumed conditions workplace exposures to glycol ethers are below levels of concern. [ABSTRACT FROM AUTHOR]

The efficacy of chlorine dioxide (ClO 2 ) in detoxifying two potential bioterrorism agents, the trichothecene mycotoxins verrucarin A and roridin A, was evaluated. In the first experiment, verrucarin A (1, 5, or 10 μ g) and roridin A (5 or 10 μg) were each inoculated onto square-inch sections of glass, paper, and cloth and exposed to 1000 ppm of ClO 2 for either 24 or 72 h at room temperature. In the second experiment, verrucarin A and roridin A (1 or 2 ppm in water) were treated with 200, 500, or 1000 ppm ClO 2 for up to 116 h at room temperature in light and dark conditions ( N = 9 per treatment for test and control). A yeast assay using Kluyveromyces marxianus was used to quantify the toxicity of verrucarin A and roridin A. Additionally, high-performance liquid chromatography was performed on selected samples. Results for the first experiment showed that ClO 2 treatment had no detectable effect on either toxin. For the second experiment, both toxins were completely inactivated at all tested concentrations in as little as 2 h after treatment with 1000 ppm ClO 2 . For verrucarin A, an effect was seen at the 500 ppm level, but this effect was not as strong as that observed at the 1000 ppm level. Roridin A toxicity was decreased after treatment with 200 and 500 ppm ClO 2 , but this was not significant until the 24-h exposure time was reached. These data show that ClO 2 (in solution) can be effective for detoxification of roridin A or verrucarin A at selected concentrations and exposure times. [ABSTRACT FROM AUTHOR]

Metoclopramide is a benzamide dopamine receptor antagonist and serotonine receptor agonist widely used as an antiemetic and gastric prokinetic drug. In addition, metoclopramide is a weak and reversible inhibitor of cholinesterases. The authors have previously shown that metoclopramide has a cholinesterase protective effect against inhibition by organophosphates (OPs). The putative mode of protective action of metoclopramide is, when administered in excess, competion for the active site of the enzyme with the more potent OP. In the present paper the authors present their results using another benzamide with weak cholinesterase inhibitory properties, tiapride (TIA). The purpose of the study was to quantify in vitro the extent of TIA-conferred protection, using dichlorvos (dichlorovinyl dimethyl phosphate; DDVP) as an inhibitor. DDVP is a moderately toxic (LD 50 in rats in the milligram range), non-neuropathic OP. The substance is responsible for a large number of accidental or suicidal exposures. Red blood cell (RBC) acetylcholinesterase (AChE) activities in whole blood and butyrylcholinesterase (BChE) activities in human plasma were measured photometrically in the presence of different DDVP and TIA concentrations and IC 50 was calculated. Determinations were repeated in the presence of increasing TIA concentrations. The IC 50 of DDVP increases with the TIA concentration in a linear manner. The protective effect of TIA on cholinesterase could be of practical relevance in the treatment of OP poisoning. The authors conclude that in vivo testing of TIA as an OP protective agent is warranted. [ABSTRACT FROM AUTHOR]

The objective of this paper is to document the prevalence of indicators of acute renal injury in a series of methanol-poisoned patients treated in an intensive care unit and to discuss the possible mechanisms. This is a retrospective analysis of the medical records of 25 consecutive patients admitted to the intensive care unit after severe intentional methanol poisoning. Acute renal impairment was defined as a serum creatinine concentration higher than 177 μ mol/L and/or a urinary output on admission and for the first 24 h below 0.5 ml/kg/h. Clinical pathological signs of acute renal injury were found in 15 patients. In comparison with the 10 other patients taken as control group, the patients who developed renal injury had a lower blood pH value on admission, a higher serum osmolality, and a higher peak formate concentration. Two factors contributing to renal injury could be identified: hemolysis and myoglobinuria. The role of osmotic changes (“osmotic nephrosis”) or of a direct cytotoxic effect of formic acid remains speculative. Analysis of proteinuria suggests that proximal tubular cells may be preferentially affected. Results of histopathological evaluation of the kidney on a limited sample size (n = 5) were inconclusive but suggestive of possible hydropic changes in the proximal tubule secondary to methanol toxicity. Acute renal injury may be associated with other signs of severity in methanol poisoning, but it is almost always reversible in survivors. Indicators of acute renal injury were identified. The pathophysiology of this acute renal injury is multifactorial and far more complex than shock-related tubular necrosis. [ABSTRACT FROM AUTHOR]

As our scientific technology grows, risk assessment methods become more complex and, therefore, open to greater scientific debate. Risk assessment has always been a part of the regulatory notification and approval process for foods. However, the methodologies applied to risk assessment and decision-making have become diverse, dependent on a number of features, including the areas of the world in which one operates, the need to use cumulative risk assessment for pesticides and other ingredients or alternative risk assessment considerations for evaluating nontraditional or bioengineered foods. Diverse institutional structures within a single federal regulatory authority may tend to lead to diversity in risk outcomes that creates policy decisions that complicate and confuse the risk management process. On top of this challenge, decisions become more complicated by the need to examine beneficial factors of foods rather than the adverse effects of foods and food additives. Foods are a complex mixture of ingredients. Regulatory groups recognize the need to use new approaches for evaluating the safety and risks associated with foods and food additives, and to do so in a timely manner. The United States Food and Drug Administration (US FDA) in its need to ensure standards of "reasonable certainty of no harm" continues to explore alternative means to be responsive to petitioners as well as continue to examine scientifically validated means, e.g., quantitative structure-activity relationship (QSAR), and computer-assisted programs, within the approval process to assist in the evaluation of risks. Another means to improve the risk management process would include the cumulative risk assessment of pesticides that will, no doubt, be the beginning of more intensive efforts to understand cumulative exposures and the inherent risks from multiple pathways of exposure. The passage of the Food Quality Protection Act (FQPA) resulted in developing additional risk assessment methodologies and approaches to assess the potential for multiple exposures and risks. Addressing the international criteria used in decision-making related to foods safety assessment has resulted in acceptable intake values for food ingredients for carcinogens and noncarcinogens that, in general, tend to be more stringent in the United States compared to Europe. Clearly, the need for harmonization of risk assessment criteria and the impact of the decision process on regulatory approvals and safety assessment is a future need for the continued assurances of food safety. The topics presented in this paper are based on a symposium held in November 2002 at the annual meeting of the American College of Toxicology. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about the comparison between in vivo or Draize method and in vitro or Corrositex Assay dermal corrosion values for selected industrial chemicals.

At its 2002 annual meeting, the American College of Toxicology hosted in its series of issue sessions a symposium entitled "The Great Debate: Are Dietary Supplements Adequately Regulated to Enhance the Safety of Consumers." There were five participants in the debate, of whom three (the moderator and one advocate from either side) contributed papers. This article, reflecting the author's talk as the moderator, presents the applicable regulations, an overview, and history of the marketplaces and the range of perceived consumer safety problems. [ABSTRACT FROM AUTHOR]

A critical review finds government agencies allow, permit, license, or ignore arsenic releases to surface soils. Release rates are controlled or evaluated using risk-based soil contaminant numerical limits employing standardized risk algorithms, chemical-specific and default input values. United States arsenic residential soil limits, ∼0.4-∼40 ppm, generally correspond to a one-in-one-million to a one-in-ten-thousand incremental cancer risk range via ingestion of or direct contact with contaminated residential soils. Background arsenic surface soil levels often exceed applicable limits. Arsenic releases to surface soils (via, e.g., air emissions, waste recycling, soil amendments, direct pesticide application, and chromated copper arsenic (CCA)-treated wood) can result in greatly elevated arsenic levels, sometimes one to two orders of magnitude greater than applicable numerical limits. CCA-treated wood, a heavily used infrastructure material at residences and public spaces, can release sufficient arsenic to result in surface soil concentrations that exceed numerical limits by one or two orders of magnitude. Although significant exceedence of arsenic surface soil numerical limits would normally result in regulatory actions at industrial or hazardous waste sites, no such pattern is seen at residential and public spaces. Given the current risk assessment paradigm, measured or expected elevated surface soil arsenic levels at residential and public spaces suggest that a regulatory health crisis of sizeable magnitude is imminent. In contrast, available literature and a survey of government agencies conducted for this paper finds no verified cases of human morbidity or mortality resulting from exposure to elevated levels of arsenic in surface soils. This concomitance of an emerging regulatory health crisis in the absence of a medical crisis is arguably partly attributable to inadequate government and private party attention to the issue. [ABSTRACT FROM AUTHOR]

This paper presents the traditional approach for the evaluation of human food safety used for animal drugs intended for food animals, and describes some of the difficulties posed by antimicrobial drug resistance. Like human drugs, animal drugs must be safe and effective for the patient. However, unlike human drugs, food derived from animals treated with the animal drug must also be shown to be safe for human consumption. The Food and Drug Administration has come to realize that antimicrobial drugs used in the treatment of the food animal have the potential to create a unique residue--increased numbers of microorganism that are resistant to antimicrobial drug treatment. The traditional toxicological paradigm for chemical residues does not apply to this unique microbiological residue. Information useful to a food safety evaluation may include the potential for the animal antimicrobial drug to diminish the susceptibility of microorganisms to human antimicrobial drugs, any human medical use of the drug, relationship to other human antimicrobial drugs, and the ability of the animal drug to alter the susceptibility of relevant microorganism to important human antimicrobial drugs. Yet to be developed are standardized approaches to quantify an acceptable level of resistant microorganism in food and to mitigate the hazard to assure that there is a reasonable certainty of no harm following the consumption of the edible food derived from the treated animal. [ABSTRACT FROM AUTHOR]

The California legislature enacted a law requiring the California Environmental Protection Agency (Cal/EPA) Office of Environmental Health Hazard Assessment (OEHHA) to evaluate whether our risk assessment methodologies are adequately protective of infants and children. In addition both OEHHA and the California Air Resources Board must examine whether the Ambient Air Quality Standards set for criteria air pollutants and the health values developed for air toxics are adequately protective of infants and children. We have initiated a program to look at potential differences in response to toxicants between children and adults. We are evaluating this issue from the perspective of exposure differences as well as toxicokinetic and toxicodynamic differences between children and adults. Data on specific chemicals are rather limited. As a result, we will be pooling information to determine whether there are generic differences between children and adults that may be applicable to risk assessment in general or to risk assessment of specific classes of compounds. This paper discusses the rationale for approaching the issue of determining whether our risk assessment methods are adequate for infants and children and includes a discussion of some of the available information on both qualitative and quantitative differences in response to toxicants between children and adults or immature and mature laboratory animals. We provide examples of differences between children and adults in absorption, metabolism, and excretion of toxicants as well as qualitative differences in toxic response. [ABSTRACT FROM AUTHOR]

In contemporary society, many scientific issues involving toxicologists, epidemiologists, and other risk assessment professionals have become the topics of hotly contested legal actions. Nowhere is this more apparent than in toxic tort cases where judgements involving millions of dollars can hinge on the expert testimony provided by a toxicologist. Many of these cases involve scientific opinions that have not yet entered the mainstream of scientific thought, thus it becomes necessary for courts to place a great deal of emphasis on the reliability of science. In this paper, we analyze the scientific and legal bases of disease causation in the toxic tort context and illustrate how the emerging issue of endocrine modulation may evolve in this context. We conclude that there is an inadequate scientific basis to show personal injuries associated with exposure to a class of putative endocrine modulators. This paper is not intended to illustrate a specific case; it is intended to be a heuristic for toxicologists, risk assessors, and attorneys, who may be forced to confront these and similar issues in the course of their professional careers. [ABSTRACT FROM AUTHOR]

This paper summarizes a few in vitro methods to assess photodamage in cells irradiated with UV of various wavelengths in the presence of a number of photosensitizers. A single in vitro assay for phototoxicity (photoirritation) is not likely to be predictive because of different mechanisms of phototoxicity and diverse cellular targets for injury. A number of methods have to be combined to provide a better prediction of these phenomena. Measurement of mechanistically relevant biomarkers also represents a promising area of in vitro testing for phototoxicity, and it is also briefly reviewed in this paper. Photodynamic sensitizers, representing a large class of phototoxic agents, can now beidentified by sensitive measurement of photooxidative damage to cellular RNA and DNA. Currently, US government agencies have not identified a single in vitro assay for phototoxicity which would be acceptable for replacing an in vivo assay for regulatory purposes. [ABSTRACT FROM AUTHOR]

Whether theconstellation of various symptoms reported in various case-study reports on some patients who have had augmentation mammoplasty with silicone implants reflects a distinct, novel ''silicone syndrome''or disease is important to setting proper endpoints for theepidemiological study of this patient population. To date, epidemiology studies on breast implant patients have focused on endpoints which aretypical of connective tissuedisease, rheumatoid disease, and/or autoimmune disorders. The consensus at this time, as was recently stated in a paper authored by Food and Drug Administration (FDA) personnel, is that the weight of the evidence from existing epidemiology studies is that silicone breast implants do not appreciably, if at all, increase the risk of these types of diseases. Critics of the epidemiology database have countered that had the analysis of association in these studies been done for a ''silicone syndrome,''as opposed to the disease types which were analyzed, an association between silicone breast implantation and increased risk of ''silicone syndrome''would have been observed. In the present analysis, this question is approached from two directions: First, the available single or multi-patient case reports available in the open literaturewere evaluated. Theobjective was to definethosesymptoms/complaints that were reported in all studies or in at least 50% of the patients reported and to assign frequency distributions to individual symptoms or complaints reported in breast implant patients presenting for various complaints. By definition, if a ''siliconesyndrome''exists,then it can only becharacterized by thosesymptoms or complaints which appear with regular frequency in patients soafflicted. Second, the symptoms or complaints which were used as criteria in the existing epidemiology studies were correlated with their frequency of occurrence among single or multi-patient case-reported breast implant patients. The working hypothesis in this present study is that if the number of ''silicone syndrome''symptoms or complaints that also are symptoms of the existing epidemiology endpoints is large, then a distinct ''silicone syndrome'' is not likely to exist, and it can be concluded that existing epidemiology studies have adequately addressed the relevant issues. Also, to the extent that the frequency of symptom occurrence in ''silicone syndrome''is similar to the distribution seen for known connective tissue, rheumatoid, and/ or autoimmune diseases, this will then add to the weight of evidence that no distinct ''silicone syndrome''needs be postulated. Conversely, if a different set of symptoms or complaints occurs in silicone breast-implanted patients than is seen in patients with connective tissue diseases, this will argue that a distinct syndrome may exist. In the present study, the more recent suggestion that silicone may be broken down to silica in the body, and evidence for and against this suggestion are also discussed. The present analysis does not support the contention that a distinct ''silicone syndrome''exists, but does support the contention that the disease endpoints used in existing epidemiology studies are adequate for examining the patient population. Also, consideration of the chemistry of silicone and its potential hydrolysis or oxidative cleavage indicates that if such reactions occur in the body at any significant rate, the product will be silicic acid, a normal and necessary constituent of the body, and not silica (i.e., silicon dioxide). [ABSTRACT FROM AUTHOR]

The objective of this multiple-dose toxicity study was to assess the toxicological potential of two tripeptides, L-valyl-L-prolyl-L-proline (VPP) and L-isoleucyl-L-prolyl-L-proline (IPP), when administered once daily for 91 consecutive days to rats. The test article, powdered casein hydrolysate (CH) known to contain 0.6% VPP plus IPP, was prepared using Aspergillus oryzae protease. Prior to administration to the rats by oral gavage, the test article was suspended in sterile water. Groups of 12 male and 12 female Charles River rats were administered once daily doses of 0, 40, 200, or 1000 mg of CH (0, 0.2,1.2, or 6 mg VPP plus IPP/kg body weight [BW]). Antemortem evaluative parameters included gross observations of behavior and clinical signs; food consumption and body weight gains; ophthalmologic examinations; clinical pathology (hematology, clinical chemistry); and urinalysis. Postmortem parameters included determination of absolute and relative (to fasting body weight) organ weights and histopathological evaluation of approximately 50 organs and tissues from each animal. All rats survived until the scheduled termination of the study and no treatment-related clinical signs were observed. Food consumption was unaffected by administration of CH. All animals gained weight and there were no statistical differences between groups with respect to weight gains. There were no meaningful changes in hematological or coagulation parameters. Mid- and high-dose males (but not females) had slightly (<2%) increased mean serum chloride concentrations, but because the difference was so small and it was observed in only one sex, the authors considered its association with CH administration to be doubtful. Urinalysis revealed the occasional presence of crystals, leukocytes, and epithelial cells in animals from all experimental groups. Similarly, ophthalmic changes (lenticular clouding) were observed in both control and dosed animals. Mean relative (to body weight) kidney weight was decreased by 8 % in low-dose males and mean relative uterus weight was elevated 46% in low-dose females. Absolute organ weights were not affected. Only naturally occurring microscopic changes were observed in all groups and none could be attributed to CH administration. It was concluded that, under the conditions of these experiments, the maximally tolerated dose (MTD) and the no-observable-effect level (NOEL) for powdered CH administered once daily for 13 weeks was greater than 1000 mg/kg BW/day or greater than 6 mg of VPP plus IPP/kg BW/day. There was no evidence of target organ toxicity associated with administration of the tripeptides. This corresponds to an margin of safety (MOS) of 60 based upon current thinking regarding incorporation in food. [ABSTRACT FROM AUTHOR]

The transformation from print to digital media for scientific communication, driven in part by the growth of the Internet and the tremendous explosion in the amount of information now available to everybody, is creating fundamental changes in institutions such as publishers, libraries, and universities that primarily exist for the creation, management, and distribution of information and knowledge. Scientific, technological, and medical journals are the first publications to be completely transformed from print to digital format but monographs are beginning to appear in digital format as well and soon all communication and publishing of scientific information will be entirely electronic. In fact, this change is affecting all components of the scientific enterprise, from personal correspondence and laboratory methods to peer reviewing and the quality assessment of scientific research. Along with these radical and rapid changes in information presentation and distribution are coincident changes in the expectations of both the public and other scientists, with both groups demanding ever more rapid, open, and global access to scientific information than has been available in the past. The consequence of this revolution in the mechanics of communications technology is threatening the very existence of a number of highly regarded institutions such as intellectual property, commercial publishers, scientific societies, and academic libraries and might soon begin to threaten even the traditional university. [ABSTRACT FROM AUTHOR]

This companion article to the History of the American College of Toxicology also is written in celebration of the 25th Anniversary of the American College of Toxicology (ACT). It relates how the official journal of the College evolved from a privately owned publication, theJournal of Environmental Pathology and Toxicology(JEPT), into publications owned and managed by the College and its Board, for the first 17 years as theJournal of the American College of Toxicology(JACT) and currently asThe International Journal of Toxicology(IJT). It relates how the first journal focused on toxicological studies, potential cancer causes and concerns associated with environmental contamination and chemical exposure safety issues. It tells how this journal was replaced by one more broadly based that addressed multiple industries and regulatory approaches, accepted previously unpublishable“no-effect”studies, so important in eliminating unwarranted animal use, and provided review articles, rather than only original research. It also described how the JACT evolved into an international journal finally recognized for its quality reviews and peer-reviewed research. Each of the three journals that represented the College is described, as well as interesting events associated with their development and publication, including the activities and contributions of the first four editors in chief, Drs. Myron A. Mehlman, Mildred S. Christian, Robert M. Diener and Harihara Mehendale.1Mildred S. Christian, PhD, Fellow, ATS, is the Founding Editor of theJournal of the American College of Toxicology. [ABSTRACT FROM AUTHOR]

The concept of hormesis has been receiving greater interest in the biomedical and toxicological research communities over the past decade. Of particular importance has been how the hormesis concept may affect risk assessment practices, litigation, and regulation. This paper identifies and discusses what may be the first application of the hormesis concept in environmental assessment and litigation. This occurred in California within the context of an assessment of alleged continuing smelter contamination nearly a century ago. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor of the 'International Journal of Toxicology,' responding to the paper 'Safety Assessment of the Mycotoxin Cyclopiazonic Acid,' by G.A. Burdock and W.G. Flamm. Authors' identification of an overall no-observable-effect level for cyclopiazonic acid in pigs of 1 milligram/kilogram of body weight per day; Flaws in the determination of the gastrointestinal toxicity.

Exposures which can induce multiple chemical sensitivity (MCS) involve symptomatic, usually repeated, exposures to pesticides, solvents, combustion products, remodeling, sick buildings, carbonless copy paper (occupational heavy use) and other irritants and petrochemicals. Accompanying toxic injury often involves the immune, endocrine and nervous systems as well as impairments in detoxification, energy and neurotransmitter metabolism, protein, mineral, and other nutrient deficiencies and gastrointestinal changes such as candida, parasites, reduced chymotrypsin (marker enzyme for reduced pancreatic enzyme function), gluten intolerance, and reduced Secretory IgA. Chronic cortisol elevation leading to adrenal insufficiency if not corrected is common. Such elevation can lead to protein and mineral deficiencies with increased osteoporosis and reduced steroid precursors for normal estrogen and testosterone production. Detoxification changes often involve reduction in one or more Phase II pathways which causes excess free radical production. Impaired digestive enzymes can reduce breakdown of foods, with larger more antigenic molecules being absorbed and consequent food intolerances. Many of these conditions are treatable. There is extensive overlap of MCS with Chronic Fatigue Syndrome and Fibromyalgia which may be one condition in many cases. Current occupational exposure limits are not health based and thus may not prevent MCS and are totally inadequate to accommodate sensitive persons. Warning symptoms indicating increased risk for MCS onset include repeated headache, eye and respiratory irritation and fatigue. Eliminating exposures which cause repeated symptoms is a critical strategy for preventing sensitization and MCS. It also significantly reduces the degree of disability in persons with MCS, the single most important factor from the literature. Affected persons with disability can utilize the Americans With Disability Act to request reasonable accommodations for work, home (condo, apartment), and school. [ABSTRACT FROM AUTHOR]

Understanding the criteria journalists use when deciding whether something is newsworthy provides insights into what toxicological data and risk-related information gets reported. Although the criteria are common to all media, the level of depth in reporting varies, based on the type of media outlet involved-ranging from daily, general circulation newspapers to the specialized media, including on-line publications. This paper addresses five aspects of the media's perspective on toxicology, risk, and the law. The following questions are addressed. What makes something newsworthy? What is the role of the media in toxicology, risk, and the law? What are common barriers to getting toxicology news reported? What are some potential solutions for overcoming these barriers? What are some take-home tips that toxicologists could use to strengthen their relationships with journalists? [ABSTRACT FROM AUTHOR]

Presents abstracts of research papers presented at the 19th annual meeting of the American College of Toxicology held on November 8-11, 1998. Human corneal epithelial cell lines as in vitro models for evaluating eye irritation; Strategic use of the stress gene heme oxygenase-1 as an index in evaluating and screening drugs and chemicals for ocular formulations.

Presents the abstracts of research papers presented at the 18th Annual Meeting of the American College of Toxicology. Animal Isolation and Containment; Status of Drug Safety-Related ICh Topics; Environmental Justice.

The evaluation of health risk from chemical exposure is evolving in concept and practice. The ability to sensitively detect levels of chemicals in the environment has served as the traditional foundation for determining exposure levels and consequent health risks. More recently, however, other parameters have been constructed to probe the pathway between environmental levels of a chemical and the biological effects of subsequent exposure. Among these, two that are discussed in this paper are bioavailability and biomarker determinations. Chemicals in the environment often are associated with a medium such as airborne particulate, water, or soil. The interaction between the chemical and its medium is dependent on the physicochemical properties of the system. In some cases, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in soil, the chemical becomes partially and irreversibly bound to the medium. Animal ingestion studies of TCDD-contaminated soil suggest that some of the TCDD remains bound to the soil and does not cross the gastrointestinal barrier during digestion, and therefore only a fraction of the TCDD enters the blood and becomes bioavailable. The characterization of bioavailability provides for more accurate exposure assessment. Biomarker information potentially can validate exposure assessment information from bioavailability studies, elucidate specific biological effects from chemical exposure, and investigate genetic susceptibility issues that may increase the likelihood that an individual or population will experience increased health risks. Benzene-induced chromosome damage is discussed as an example of a significant biomarker that has demonstrated the potential for providing information useful for accurately prediction health risk. [ABSTRACT FROM AUTHOR]

Production of methemoglobin (metHb) is effective in treating or preventing cyanide intoxication due to the affinity of cyanide for metHb. This paper describes an automated method for measuring metHb in mouse blood utilizing the Roche COBA S FARA centrifugal analyzer and a modified Evelyn-Malloy procedure. Blood samples were spiked with various quantities of potassium ferricyanide to produce metHb, and automated and manual analyses of these samples were compared. Following validation of the COBA S method, two known metHb inducers, sodium nitrite and p-aminopropiophenone (PA PP), and two sulfur donor compounds, sodium thiosulfate and ICD #1021, not known to produce metHb were tested in vivo. Five mice per compound were injected IP and blood samples were analyzed periodically over a time period of approximately 2 h. The automated technique requires only a drop of blood, which allows repeated sampling from the same animal, and can be adapted for blood from different species. A nalyses are rapid and sensitive, and results are reproducible. [ABSTRACT FROM AUTHOR]

Presents abstracts of toxicology-related research papers featured at the Seventeenth Annual Meeting of the American College of Toxicology on November 10-13, 1996 in Pennsylvania. Silicone breast implants; Trends in toxicologic pathology; Preclinical safety assessment of biotechnology products.

As more in vitro nanotoxicity data appear in the literature, these findings must be translated to in vivo effects to define nanoparticle exposure risk. Physiologically based pharmacokinetic (PBPK) modeling has played a significant role in guiding and validating in vivo studies for molecular chemical exposure and can develop as a significant tool in guiding similar nanotoxicity studies. This study models the population dynamics of a single cell type within a specific tissue. It is the first attempt to model the in vitro effects of a nanoparticle exposure, in this case aluminum (80 nm) and its impact on a population of rat alveolar macrophages (Wagner et al. 2007, J. Phys. Chem. B 111:7353-7359). The model demonstrates how in vitro data can be used within a simulation setting of in vivo cell dynamics and suggests that PBPK models should be developed quickly to interpret nanotoxicity data, guide in vivo study design, and accelerate nanoparticle risk assessment. [ABSTRACT FROM AUTHOR]

Parabens is the name given to a group of p-hydroxybenzoic acid (PHBA) esters used in over 22,000 cosmetics as preservatives at concentrations up to 0.8% (mixtures of parabens) or up to 0.4% (single paraben). The group includes Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben. Industry estimates of the daily use of cosmetic products that may contain parabens were 17.76 g for adults and 378 mg for infants. Parabens in cosmetic formulations applied to skin penetrate the stratum corneum in inverse relation to the ester chain length. Carboxylesterases hydrolyze parabens in the skin. Parabens do not accumulate in the body. Serum concentrations of parabens, even after intravenous administration, quickly decline and remain low. Acute toxicity studies in animals indicate that parabens are not significantly toxic by various routes of administration. Subchronic and chronic oral studies indicate that parabens are practically nontoxic. Numerous genotoxicity studies, including Ames testing, dominant lethal assay, host-mediated assay, and cytogenic assays, indicate that the Parabens are generally nonmutagenic, although Ethylparaben and Methylparaben did increase chromosomal aberrations in a Chinese Hamster ovary cell assay... [ABSTRACT FROM AUTHOR]

Trichloroethane functions in cosmetics as a solvent. Although Trichloroethane has been reported to the Food and Drug Administration (FDA) to be used in cosmetic products, an industry survey found that it is not in current use in the cosmetic industry. Trichloroethane is considered a Class I ozone-depleting substance by the Environmental Protection Agency (EPA) and its use is prohibited in the United States, unless considered essential. The FDA has stated that Trichloroethane's use in cosmetics is considered nonessential. Trichloroethane is detected by gas chromatography, gas chromatography-mass spectrometry, and gas-liquid chromatography. In rats, Trichloroethane, whether inhaled or injected, is mostly expelled intact from the body through exhalation. A very small percentage is excreted in the urine. In humans, Trichloroethane is rapidly absorbed through the skin and eliminated in exhaled air and a very small percentage is excreted in urine. Inhaled Trichloroethane is eliminated in exhaled air. Acute oral LD50 values have been reported as follows: 12.3 g/kg in male rats; 10.3 g/kg in female rats; 11.24 g/kg in female mice; 5.66 g/kg in female rabbits; and 9.47 g/kg in male guinea pigs. Acute toxicity studies using other routes of exposure, including subcutaneous injection and inhalation, produced no evidence of significant toxicity, except at very high exposure levels. Continuous inhalation exposure of rabbits to 750 mg/m3 for 90 days did not produce any signs of toxicity. Continuous exposure of rats, guinea pigs, rabbits, and monkeys to 500 ppm Trichloroethane for 6 months did not produce any signs of toxicity. Other short-term and subchronic inhalation exposures confirmed acute and short-term exposure findings that the toxic effects of inhalation were a function of both concentration and time... [ABSTRACT FROM AUTHOR]

Polyisobutene and Hydrogenated Polyisobutene are homopolymers of isobutene. These ingredients are produced in a wide range of molecular weights. Polybutene is a chemically related cosmetic ingredient previously determined to be safe as used in cosmetic products. Polyisobutene is used in cosmetic products as a binder, film former, and nonaqueous viscosity-increasing agent. Hydrogenated Polyisobutene functions as a skin-conditioning agent—emollient and nonaqueous viscosity-increasing agent with a wide range of uses in cosmetic formulations. The estimated octanol water partition coefficient for Hydrogenated Polyisobutene and Polybutene is log Kow of 13.27 and the estimated water solubility was 5.6 × 10-3 ng/L for Hydrogenated Polyisobutene and Polybutene. Acute oral toxicity testing demonstrated no effects other than lethargy in one rat study. The oral LD50 was > 5.0 g/kg in rats. No short-term or subchronic animal toxicity data were available. A 2-year chronic oral toxicity study of Polybutene revealed no gross or microscopic pathological changes, and no changes in body weights or food consumption, hematological results, urology, or tumor formation that could be correlated with Polybutene ingestion, except that in the 20,000 ppm group, three out of six males that died between weeks 17 and 24 exhibited hematuria. In a 2-year chronic oral toxicity study of Polybutene in Beagle dogs, no abnormalities in body weight, food consumption, survival, behavioral patterns, hematology, blood chemistry, urinalysis, liver function, gross and histopathologic examinations, or organ weights and ratios were reported. In a three-generation reproductive study in Charles River albino rats that ingested Polybutene, none of the animals in successive generations differed from controls with regard to weight gain, litter size, the number of stillborn, and the number of viable pups during lactation... [ABSTRACT FROM AUTHOR]

To evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2), a 13-week gavage toxicity study was conducted in Sprague-Dawley rats (10/sex/group). Test subjects received either dihydrocapsiate, 100, 300, or 1000 mg/kg/day, or vehicle by gavage and were observed for antemortem and postmortem signs of toxicity, which included changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. No changes attributable to the test article were observed in clinical signs, body weights, food consumption, water intake, ophthalmology, urinalysis, hematology, or histopathology. A number of sporadic blood chemistry differences were observed at the high dose between treated and controls, but were not of toxicological significance and were not attributable to the test article. These included increased alanine aminotransferase (ALT) activity in males; increased total protein in males and females; increased calcium, percentage of albumin fraction, and A/G (albumin/globulin) ratio and decreased percentage of γ-globulin fraction in female rats. An effect, which was attributable to the test article, was increases in both absolute and relative liver weights in the high dose (both sexes). In the absence of histopathological changes attributable to the test article, the liver weight changes were considered adaptive (physiological) in nature and not of toxicological significance. It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 1000 mg/kg/day for both male and female rats in this 13-week gavage study. [ABSTRACT FROM AUTHOR]

Dihydrocapsiate, (4-hydroxy-3-methoxybenzyl 8-methylnona- noate; CAS No. 205687-03-2) is a naturally occurring capsinoid compound found in nonpungent chili peppers. Although the safety of synthetically produced dihydrocapsiate has been previously evaluated, the purpose of this 13-week gavage toxicity study is to evaluate dihydrocapsiate produced with a slightly modified manufacturing process. Sprague-Dawley rats, 10 rats/sex/group, 6 weeks of age at study initiation, were administered the dihydrocapsiate daily by gavage at dose levels of 0 (vehicle), 100, 300, or 1000 mg/kg/day. The rats were observed for antimortem and postmortem signs of toxicity, including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. There were no changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, or blood chemistry that were attributable to the administration of dihydrocapsiate. The only change observed attributable to the dihydrocapsiate administration involved the liver and that change occurred only at the high dose (1000 mg/kg). Both sexes had an increase in organ weights, but this increase correlated with a change in histopathology (i.e., hepatocyte hypertrophy) only in the males. No dihydrocapsiate-related histopathological changes were observed in males at doses ≤ 300 mg/kg or in females at any of the doses tested (≤ 1000 mg/kg). It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 300 mg/kg/day for male rats and 1000 mg/kg/day for female rats in this 13 week gavage study. [ABSTRACT FROM AUTHOR]

Robust assessments of the nonclinical safety profile of biopharmaceuticals are best developed on a scientifically justified, case-by-case basis, with consideration of the therapeutic molecule, molecular target, and differences/similarities between nonclinical species and humans (ICH S6). Significant experience has been gained in the 10 years ensuing since publication of the ICH S6 guidance. In a PhRMA-FDA-sponsored workshop, “Nonclinical Aspects of Biopharmaceutical Development,” industry and US regulatory representatives engaged in exploration of current scientific and regulatory issues relating to the nonclinical development of biopharmaceuticals in order to share scientific learning and experience and to work towards establishing consistency in application of general principles and approaches. The proceedings and discussions of this workshop confirm general alignment of strategy and tactics in development of biopharmaceuticals with regard to such areas as species selection, selection of high doses in toxicology studies, selection of clinical doses, the conduct of developmental and reproductive toxicity (DART) studies, and assessment of carcinogenic potential. However, several important aspects, including, for example, appropriate use of homologues, nonhuman primates, and/or in vitro models in the assessment of risk for potential developmental and carcinogenic effects, were identified as requiring further scientific exploration and discussion. [ABSTRACT FROM AUTHOR]

The safety profile of a recently described novel archaeal lipid mucosal vaccine adjuvant and delivery (AMVAD) system capable of eliciting robust antigen-specific mucosal and systemic immune responses was evaluated in female Balb/c mice (10/group) using ovalbumin (OVA) antigen. Mice were intranasally immunized (0, 7, and 21 days) with a vaccine comprising 1 μg OVA (0.05 mg/kg body weight) formulated in 0.04 mg total polar lipids extract (2.17 mg/kg body weight) of Methanobrevibacter smithii constituting the AMVAD system. Control groups were similarly immunized with 10-fold higher AMVAD vaccine dose (0.54 mg OVA and 21.7 mg lipid per kg), saline, 10 μg OVA in saline, or 0.04 or 0.4 mg lipid constituting empty AMVAD (no OVA) in saline, or were naive mice. Clinical signs, rectal temperature, and body weight were monitored once daily or as appropriate. Half the mice in each group were euthanized at 2 days after the first immunization. Blood was collected for clinical chemistry analyses. Major organs (heart, lungs, kidneys, liver, spleen, thymus, and brain) were examined macroscopically and histologically. The remaining mice were euthanized at 29 days and blood and organs collected for analyses as done at 2 days. Feces collected at 27 days, and sera, bile, and nasal lavage at 29 days, were assayed for antibody responses. Based on clinical symptoms, temperature, body weight changes, serum clinical chemistry, and tissue histopathology, there were no overt toxicities associated with OVA/AMVAD or empty AMVAD vaccines. There were no antibodies elicited against the lipids comprising the AMVAD system. These results demonstrate that at 10-fold excess dose of that required for vaccine efficacy, intranasally administered AMVAD vaccine appears to be relatively safe. [ABSTRACT FROM AUTHOR]

Cyclotrimethylenetrinitramine (RDX), a commonly used military explosive, was detected as a contaminant of soil and water at Army facilities and ranges. This study was conducted to determine the relative oral bioavailability of RDX in contaminated soil and to develop a method to derive bioavailability adjustments for risk assessments using rodents. Adult male Sprague-Dawley rats preimplanted with femoral artery catheters were dosed orally with gelatin capsules containing either pure RDX or an equivalent amount of RDX in contaminated soils from Louisiana Army Ammunition Plant (LAAP) (2300 μ g/g of soil) or Fort Meade (FM) (670 μ g/g of soil). After dosing rats, blood samples were collected from catheters at 2-h intervals (2, 4, 6, 8, 10, and 12) and at 24 and 48 h. RDX levels in the blood were determined by gas chromatography. The results show that the peak absorption of RDX in blood was 6 h for neat RDX (1.24 mg/kg) and for RDX from contaminated soil (1.24 mg/kg) of LAAP. Rats dosed with RDX-contaminated FM soil (0.2 mg/kg) showed peak levels of RDX in blood at 6 h, whereas their counterparts that received an identical dose (0.2 mg/kg) of neat RDX showed peak absorption at 4 h. The blood levels of absorbed RDX from LAAP soil were about 25% less than for neat RDX, whereas the bioavailability of RDX from FM soils was about 15% less than that seen in rats treated with neat RDX (0.2 mg/kg). The oral bioavailability in rats fed RDX in LAAP soil and the FM soil was reduced with the neat compound but decrease in bioavailability varied with the soil type. [ABSTRACT FROM AUTHOR]