Evaluation Of Human Risk Research Articles

Herbicides in the tissues and organs of different fish species (Kalk Bay harbour, South Africa): occurrence, levels and risk assessment

This study evaluated the levels and concentrations of five selected herbicides in fish species wild-caught and sold at Kalk Bay harbour, Cape Town, South Africa. The samples were analysed using gas chromatography coupled with mass chromatography. The concentration detected in the fish samples ranged from atrazine: not detected (nd) to 66 ng/g dry weight (dw), simazine: nd to 158 ng/g dw, alachlor: nd to 48 ng/g dw, metolachlor: nd to 94 ng/g dw and butachlor: nd to 9 ng/g dw. The ecological risk assessment results were greater than 0.5 for acute risk and 1.0 chronic risk, while the human risk evaluation indicates that the concentration of these chemical contaminants in the selected fish samples showed that there is possibility of developing cancers should the fishes be consumed over a period of time. Therefore, there is need to set up an appropriate guideline and monitoring of the use, storage and disposal of these chemicals in Western Cape Province and South Africa generally.

Evaluation of human risks of surface water and groundwater contaminated with Cd and Pb in the southern El-Minya Governorate, Egypt

Abstract. Water pollution with cadmium (Cd) and lead (Pb) is a worldwide concern because of their health impact. Determination of their concentrations and potential human health risks in surface water and groundwater in the southern El-Minya Governorate, Egypt, is the main aim of this study. Fifty-five samples were collected, 30 surface water samples and 25 groundwater samples. The samples were analyzed using atomic absorption spectrometry to determine Cd and Pb contents. Their levels in surface water and groundwater exceeded the maximum allowable level for drinking water set by the World Health Organization (WHO). The hazard quotient showed that the surface water and groundwater may pose a health risk to residents, especially to children.

Prioritization of Flame Retardants for Human Risk Evaluation Based on Population Levels and Toxicity

Due to flammability standards, flame retardants (FRs) are widely used in consumer products and building materials. International restrictions on the use of polybrominated diphenyl ethers (PBDEs) ha...

Human factors risk assessment and management: Process safety in engineering

Abstract Human factors are the primary factors leading to accidents. Therefore, managing human factors is an important way to prevent accidents. This paper aims to introduce a new method to assess and manage human factors. First, the accident causation model was improved based on Reason’s “Swiss-cheese” model, which was then combined with the Human Factor Analysis and Classification System (HFACS) to establish the human factors risk assessment model. The evaluation model includes 5 levels (organization influence, unsafe supervision, preconditions for unsafe acts, unsafe acts, and emergency influence) and 25 human factors. In the risk assessment process, the set pair analysis method was used to calculate the connection number and the partial connection number of each factor, level and whole system. The safety score and risk development interval were calculated by using the connection number, and the risk grade is determined. Thus, the dynamic quantitative evaluation of human risk is realized. By using the partial connection number, the risk development trend of each factor is predicted. Due to the lack of human managed enterprises, the safety status of people is approximately discrete. Therefore, this paper establishes the SPA–Markov chain risk prediction model to predict human risk. The verification results show that the prediction error is less than 2%. This indicates that the prediction model can be applied in practice. To reduce human risk, ABC analysis and the “S-O-R” model were used for human risk management. The application results show that this method has a significant effect on improving human safety factors. Finally, this paper summarizes 12 common unsafe factors and their effective safety “stimulus” measure, researching the accident path. According to the organizational level and individual level of human factors, different kinds of human factors management methods are suggested.

Soil versus plant as indicators of agroecosystem pollution by potentially toxic elements

AbstractThe major route of potentially toxic elements (PTEs) to humans is the intake through food. They enter the food chain principally by plants uptake from the soil and, to a less extent, through foliar deposition. The soil‐to‐plant transfer as part of the biogeochemical cycle of these elements is a complex and hardly predictable process. In this study, we investigated the capability of soils and plants to indicate PTEs inputs in an intermingled urban‐rural landscape of south Italy affected by legal and illegal waste disposal and dumping. For this aim, 172 agricultural soil and plant (edible part) samples were collected in pairs from 47 municipalities and analyzed for 12 PTEs (As, Be, Cd, Co, Cu, Cr, Ni, Pb, Se, Tl, V, Zn). Soil extractions with 1 M NH4NO3 and 0.05 M EDTA pH 7 were applied to assess PTEs bioavailability. Results were examined according to plant species and main soil chemical properties. For Pb and Cd, the soil‐to‐plant transfer factors (TF) and the corresponding soil benchmark concentrations were also investigated. Zinc, Cu, Cd, and Pb were the only PTEs of anthropic origin severely polluting from 10 to 16% of the soils, but only in a very few cases exceeded physiological or EU legal critical values in the edible part of the plants. An evaluation of human risk due to the ingestion of these elements was tried; no risk for consumers for Zn, Cu, and Pb, while for Cd three values slightly exceeded the tolerable daily intake. Therefore, we conclude that crops cultivated in the studied area could represent only a moderate risk for human health. No correlation was found between soil and plant data, which likely highlights different pollution inputs. A large variability characterized the Pb and Cd TF, making it difficult to establish a unique benchmark concentration for the studied agricultural soils.

Toxicology Testing of Drug Combinations Does Not Add Significant Value to Human Risk Evaluation Beyond What is Known for the Individual Agents

This study describes the characterization of pharmacokinetic (PK) properties of acetaminophen (APAP) in the Two-Organ-Chip platform (2-OC), a two-chamber device able to cultivate 3D tissues under flow. The APAP intestinal absorption and hepatic metabolism were emulated by human intestine and liver equivalents respectively. The intestinal barrier was produced using Caco-2 and HT-29 cells. The liver spheroids were produced with HepaRG and HHSTeC cells. Cell viability and toxicity were assessed by MTT assay, histology, confocal immunohistochemistry, and multiparametric high content analysis. Gene expression of intestine and liver equivalents were assessed by real-time PCR. Three assemblies of Microphysiological System (MPS) were applied: Intestine 2-OC, Liver 2-OC, and Intestine/Liver 2-OC. The oral administration was emulated by APAP placement over the apical side of the intestinal barrier and the intravenous routes were mimic by the application in the medium. Samples were analyzed by HPLC/UV. APAP 12 μM or 2 μM treatment did not induce cytotoxicity for the intestinal barrier (24 h time-point) or for the liver spheroids 12 h time-point), respectively. All preparations showed slower APAP absorption than reported for humans: Peak time (Tmax) = 12 h for Intestine 2-OC and 6 h for Intestine/Liver 2-OC in both static and dynamic conditions, against reported Tmax of 0,33 to 1,4 h after oral administration to humans. APAP metabolism was also slower than reported for humans. The APAP half-life (T1/2) was 12 h in the dynamic Liver 2-OC, against T1/2 = 2 ± 0,4 h reported for humans. Samples taken from the Liver 2-OC static preparation did not show APAP concentration decrease. These findings show the MPS capability and potential to emulate human PK properties and highlight the critical role of mechanical stimulus over cell functionality, especially by demonstrating the clear positive influence of the microfluidic flow over the liver equivalents metabolic performance.

Progress of in vivo studies on the systemic toxicities induced by titanium dioxide nanoparticles.

Titanium dioxide nanoparticles (TiO2 NPs) are inorganic materials with a diameter of 1-100 nm. In recent years, TiO2 NPs have been used in a wide range of products, including food, toothpaste, cosmetics, medicine, paints and printing materials, due to their unique properties (high stability, anti-corrosion, and efficient photocatalysis). Following exposure via various routes including inhalation, injection, dermal deposition and gastrointestinal tract absorption, NPs can be found in various organs in the body potentially inducing toxic effects. Thus more attention to the safety of TiO2 NPs is necessary. Therefore, the present review aims to provide a comprehensive evaluation of the toxic effects induced by TiO2 NPs in the lung, liver, stomach, intestine, kidney, spleen, brain, hippocampus, heart, blood vessels, ovary and testis of mice and rats in in vivo experiments, and evaluate their potential toxic mechanisms. The findings will provide an important reference for human risk evaluation and management following TiO2 NP exposure.

Titanium dioxide nanoparticles and the oral uptake-route

AbstractTitanium dioxide (TiO2) is a common additive that is increasingly used in consumer products, food, pharmaceutical dosage forms and cosmetic articles. However, due to size reduction of TiO2 particles from the microscale to the nanoscale, application areas of this material are expanding, especially in the food sector, which makes investigations of nano-TiO2 crucial. This review focuses on two important topics of current research regarding the oral pathway: 1) anatomy of the orogastrointestinal tract, composition of epithelial and mucus layer, and pH changes; 2) cell entry mechanisms, cytotoxicity and translocation. Sufficient knowledge on the oral uptake route is not yet available but is highly needed for human risk evaluation.

Effects of methylmercury exposure on neuronal differentiation of mouse and human embryonic stem cells

The establishment of more efficient in vitro approaches has been widely acknowledged as a critical need for toxicity testing. In this study, we examined the effects of methylmercury (MeHg), which is a well-known developmental neurotoxicant, in two neuronal differentiation systems of mouse and human embryonic stem cells (mESCs and hESCs, respectively). Embryoid bodies were generated from gathering of mESCs and hESCs using a micro-device and seeded onto ornithine–laminin-coated plates to promote proliferation and neuronal differentiation. The cells were exposed to MeHg from the start of neuronal induction until the termination of cultures, and significant reductions of mESCs and hESCs were observed in the cell viability assays at 1,10,100 and 1000nM, respectively. Although the mESC derivatives were more sensitive than the hESC derivatives to MeHg exposure in terms of cell viability, the morphological evaluation demonstrated that the neurite length and branch points of hESC derivatives were more susceptible to a low concentration of MeHg. Then, the mRNA levels of differentiation markers were examined using quantitative RT-PCR analysis and the interactions between MeHg exposure and gene expression levels were visualized using a network model based on a Bayesian algorithm. The Bayesian network analysis showed that a MeHg-node was located on the highest hierarchy in the hESC derivatives, but not in the mESC derivatives, suggesting that MeHg directly affect differentiation marker genes in hESCs. Taken together, effects of MeHg were observed in our neuronal differentiation systems of mESCs and hESCs using a combination of morphological and molecular markers. Our study provided possible, but limited, evidences that human ESC models might be more sensitive in particular endpoints in response to MeHg exposure than that in mouse ESC models. Further investigations that expand on the findings of the present paper may solve problems that occur when the outcomes from laboratory animals are extrapolated for human risk evaluation.

Toxicological Effects of Titanium Dioxide Nanoparticles: A Review of In Vivo Studies

The essence of nanotechnology is the production of nanoparticles (NPs) with unique physicochemical properties allowing worldwide application in new structures, materials, and devices. The consequently increasing human exposure to NPs has raised concerns regarding their health and safety profiles. Titanium dioxide (TiO2) has been reported to induce adverse pulmonary responses in exposed animals. However, the potential more dangerous biological activities of TiO2 NPs compared to their fine‐sized counterparts are not fully understood. Therefore, this work is aimed to provide a comprehensive evaluation of the toxic effects induced by TiO2 NPs in in vivo experiments. It is intended to deeply understand the toxicological behaviour of TiO2 NPs and to predict potential human health effects. Moreover, it may be an instrument to extrapolate relevant data for human risk evaluation and management and to identify those critical aspects that deserve great attention in future population and epidemiologic research.

Commentary on “Evaluation of Possible Carcinogenic Risk to Humans Based on Liver Tumors in Rodent Assays

Dr. Cohen’s commentary provides an excellent review of human risk evaluation for rodent liver carcinogens, based on the mode of action (MOA) framework. This approach identifies key steps in the pathogenesis of neoplasia and then determines whether these key steps are likely to occur in humans exposed to the test article. While this provides an excellent basis for assessment of human risk for rodent carcinogens, it does not provide a compelling argument for application in the opposite direction, that is, that all relevant modes of action for all rodent carcinogens have been identified or could be identified in shorter term (e.g., thirteen-week) studies. The two-year rodent bioassay (carcinogenicity study) has recently been criticized as being imprecise and too costly. The costs involve time and animal use as well as monetary costs for laboratory activities and professional evaluation. The bioassay is also criticized as being overly sensitive, lacking specificity, and not necessarily defining human risk. One has to agree that the two-year rodent bioassay is not a perfect model, if one defines a perfect model as having 100% sensitivity and 100% specificity for the target outcome. By that standard, there are no perfect models. Even well-controlled tests in humans are not perfect for outcomes in all humans because of variability in genetic makeup and environment that may not be evident as being relevant a priori. This is more likely to occur when dealing with new molecular targets in pharmaceutical development. The rodent bioassay is a hazard identification tool and does not necessarily provide all information needed for risk assessment. Dr. Cohen reviews the evolution of the MOA framework as applied to rodent carcinogenicity studies and applies this to rodent liver carcinogens. The MOA framework has been applied previously in determining the relative human risk for rodent liver tumors (Holsapple et al. 2006). The application of the MOA framework depends on the identification of key events necessary for development of neoplasms in the rodent model. Note that this is not necessarily the mechanism of action, the actual molecular events associated with primary or secondary alterations in DNA, but key events in the progression of tumor development. Dr. Cohen points out that carcinogenicity is due to two basic processes, direct genotoxicity and nongenotoxic (epigenetic) effects, which result in increased cell replications that lead to an increased chance of spontaneous genetic defects. Potential relevant epigenetic effects also include changes in cell cycle control, genetic repair mechanisms, or signals for cellular differentiation that allow cells with genetic alterations to survive. These effects may not be associated directly with increased cell replications. A basic premise of Dr. Cohen’s argument is that all key events associated with development of liver neoplasms in rodents can be detected in shorter term (thirteen-week) studies (Allen et al. 2004). This is likely correct, at least for all key events identified to date. Since the liver is a common site of carcinogenicity in the rodent, carcinogenic effects in the liver have been extensively studied, and the key events associated with most rodent carcinogens have been identified. It should be noted that the reference Dr. Cohen cites (Allen et al. 2004) involves chemicals in tests in the National Toxicology Program. Most effects of these chemicals are likely associated with chemical toxicity or nonspecific epigenetic events (e.g., enzyme induction) and do not represent novel pharmacologic target mediated events. Dr. Cohen also points out that detection of these changes has high sensitivity but low specificity, which would then be considered to be hazard identification rather than risk assessment. His approach then applies the MOA process to assess potential human cancer risk of these identified key events and may involve additional mechanistic studies. Dr. Cohen’s proposal is in line with the current direction of proposals for improvements in toxicology testing recently proposed by the National Research Council (2007; reviewed by Krewski et al. 2009). This vision of testing is to eventually move to toxicology testing in vitro that tests critical pathways of human toxicity. The envisioned outcome of this exercise Address correspondence to: Gerald G. Long, Experimental Pathology Laboratories Inc, P.O. Box 169, Sterling, VA 20167; e-mail: glong@epl-inc.com. Abbreviations: FDA, Food and Drug Administration; GLP-1, glucagonlike peptide 1; MOA, mode of action; PPAR, peroxisome proliferatoractivated receptor.

Chemicals exposure: Scoring procedure and uncertainty propagation in scenario selection for risk analysis

The present work aims to obtain a methodology to score dangerous chemical pollutants related to the exposure scenarios of human risk and to evaluate the uncertainty of the scoring procedure. For chronic human risk evaluation, the problem of characterizing the most dangerous situation is posed. In this paper a ranking procedure was assessed in order to score eight pollutants through a “ scoring model” approach. The scoring system was organized in a matrix form in order to put in evidence the strong connection between properties of the substances and exposure scenarios. Two different modelling approaches were considered as cause–effect relationships for risk evaluation: Risk Based Corrective Action (RBCA) and a “mobility and degradation matrix”. The first takes into account the exposure pathways (soil, water and air) and the exposure routes (inhalation, ingestion and dermal contact), while the second considers the capacity of the chemicals to move into the environment and the rate of degradation associated with chemical–biological processes as measure of persistence. A specific score for each chemical along its uncertainty were evaluated. The uncertainty of the scoring procedure was evaluated by using the law of propagation of uncertainty; it was used to estimate the global uncertainty related to each exposure pathway for the eight substances for both models. Results of scoring as well uncertainty put in evidence that the ordering of chemicals is strongly dependent on the model used and on the available data. The procedure is simple and easy to use and its implementation allows users to compare several and several compounds.

Air pollution and mutations in the germline: are humans at risk?

Genotoxic air pollution is ubiquitous in urban and industrial areas. A variety of studies has linked human exposure to air pollution with a number of different somatic cell endpoints including cancer. However, the potential for inducing mutations in the human germline remains unclear. Sentinel animal studies of germline mutations at tandem-repeat loci (specifically minisatellites and expanded simple tandem repeats) have recently provided proof of principle that germline mutations can be induced in vertebrates (birds and mice) by air pollution under ambient conditions. Although humans may also be susceptible to induced germline mutations in polluted areas, uncertainties regarding causative agents, doses, and mutational mechanisms at repetitive DNA loci currently preclude extrapolation from animal data to the evaluation of human risk. Nevertheless, several recent studies have linked air pollution exposure to DNA damage in human sperm, indicating that our germ cells are not impervious to the genotoxic effects of air pollution. Thus, both sentinel animal and human studies have raised the possibility that ambient air pollution may increase human germline mutation rates, especially at repetitive DNA loci. Given that some human genetic conditions appear to be modulated by length mutations at tandem-repeat loci (e.g. HRAS1 cancers, type 1 diabetes, etc.), there is an urgent need for extensive study in this area. Research should be primarily focused upon: (1) the direct measurement of mutation frequencies at repetitive DNA loci in human male germ cells as a function of air pollution exposure, (2) large-scale epidemiology studies of inherited disorders and tandem-repeat associated genetic conditions and air pollution, and (3) the characterization of mutational mechanisms at hypervariable tandem-repeat loci.

Human health risks of petroleum-contaminated groundwater

The volatile organic compounds Benzene, Toluene, Ethylbenzene and Xylene (BTEX) are commonly found in petroleum derivatives and, at relatively high levels, can be associated with human health risks. Due to industrial activities, accidental petroleum spills are the main route of soil and groundwater contamination. The aim of the present study was to evaluate the indoor health risks due to tap water consumption contaminated by BTEX. BTEX indoor exposure can occur through three principal pathways: inhalation, ingestion and dermal absorption. A multiphase and multicomponent model was used to simulate BTEX transport in groundwater. For evaluation of human risks due to the use of contaminated tap water, a mathematical model was elaborated. BTEX concentrations in a drinking well were obtained as a function over time. These concentrations were used to obtain the exposure due to the use of water from the contaminated drinking well. In addition to showing the highest concentration in water, benzene was the compound that remained for a longer period before being completely degraded. For all the evaluated BTEX, oral ingestion was also the main pathway of exposure for adults, whereas the contribution of inhalation and oral exposition in children were seen to be of the same magnitude. The sensitivity analysis of BTEX total dose for adults showed that direct ingestion was the most significant factor, followed by shower time, volume of the shower room, inhalation rate, and shower flow rate. For children, the most significant variable was also direct ingestion, followed by shower time, volume of the shower room, and body weight. In the current design situation, there would not be any health risks by the use of BTEX-contaminated water to the general population living in the neighborhood of the petroleum spill. Therefore, no remediation measures in the area of the spill would be necessary. The present results indicate that the design of a good scenario can perform an accuracy risk assessment. This model can serve as a useful tool for predicting indoor exposure to substances for which no direct data are available, reducing monitoring efforts and observing how different processes affect outcomes. These preliminary data allow the establishment of a basis for further investigations focusing on efficiently recovering petroleum from contaminated sites.

CYP1A Induction and Human Risk Assessment: An Evolving Tale of in Vitro and in Vivo Studies: TABLE 1

CYP1A1 and 1A2 play critical roles in the metabolic activation of carcinogenic polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines/amides (HAAs), respectively, to electrophilic reactive intermediates, leading to toxicity and cancer. CYP1As are highly inducible by PAHs and halogenated aromatic hydrocarbons via aryl hydrocarbon receptor-mediated gene transcription. The impact of CYP1A induction on the carcinogenic and toxic potentials of environmental, occupational, dietary, and therapeutic chemicals has been a central focus of human risk evaluation and has broadly influenced the fields of cancer research, toxicology, pharmacology, and risk assessment over the past half-century. From the early discovery of CYP1A induction and its role in protection against chemical carcinogenesis in intact animals, to the establishment of CYP1A enzymes as the principal cytochromes P450 for bioactivation of PAHs and HAAs in in vitro assays, to the recent realization of an essential protective role of CYP1A in benzo[a]pyrene-induced lethality and carcinogenesis with CYP1A knockout mice, the understanding of the interrelation between CYP1A induction and chemical safety has followed a full circle. This unique path of CYP1A research underscores the importance of whole animal and human studies in chemical safety evaluation.

Aflatoxin M 1 absorption and cytotoxicity on human intestinal in vitro model

Aflatoxin M 1 (AFM 1) is the principal hydroxylated Aflatoxin B 1 (AFB 1) metabolite and is detected in milk of mammals, after consumption of feed contaminated with AFB 1. As it is classified as probable human carcinogen (group 2B of the IARC), most countries have regulated its maximum allowed levels in milk in order to reduce AFM 1 risk (50 ng/kg the EU and 500 ng/kg in the USA). It was demonstrated that if AFB 1 must be converted into its reactive epoxide to exert its effects, and the protein binding may play an important role in its cytotoxicity. Conversely, the AFM 1 epoxidation in human liver microsomes is very limited and studies with human cell line (MCL5), expressing or not expressing cytochrome P450 enzymes, demonstrated a direct toxic potential of AFM 1 in absence of metabolic activation. For this reason, while AFM 1 is generally considered a detoxification product of AFB 1 relatively to carcinogenicity and mutagenicity property, this is not always true for cytotoxicity activity. Aim of this work is to evaluate the intestinal absorption of AFM 1 using a human in vitro model, the Caco-2 cell line. Either the parental Caco-2 cell line or its derived clone TC7, with higher metabolic competence, have been used. They were treated with different concentrations of AFM 1, that mirror the milk contamination level (0.3–32 nM corresponding to 10–10,000 ng/kg), either in undifferentiated or in differentiated phase of growth. After 48 h of treatment in serum free medium, a dose dependent absorption of AFM 1 has been detected in both cell lines, especially in differentiated cells, while, no appreciable effects on cell viability were observed, except for a general cellular suffering, revealed by LDH release, particularly evident in the undifferentiated cells. As well, no metabolites or AFM 1 conjugates have been detected. The present results may be crucial for the evaluation of human risk to AFM 1 exposure, in particular for children's population, due to their large use of milk and derivatives.

Toxicity evaluation of surface water treated with different disinfectants in HepG2 cells

It is well known that water disinfection through chlorination causes the formation of a mixture of disinfection by-products (DBPs), many of which are genotoxic and carcinogenic. To demonstrate the formation of such compounds, a pilot water plant supplied with water from Lake Trasimeno was set up at the waterworks of Castiglione del Lago (PG, Italy). The disinfectants, continuously added to prefiltered lake water flowing into three different basins, were sodium hypochlorite, chlorine dioxide and peracetic acid, an alternative disinfectant used until now for disinfecting waste waters, but not yet studied for a possible use in drinking water treatment. The aim of this study was to evaluate the formation during the disinfection processes of some toxic compounds that could explain the genotoxic effects of drinking waters. Differently treated waters were concentrated by solid-phase adsorption on silica C 18 columns and toxicity was assessed in a line of human hepatoma cells (HepG2), a metabolically competent cellular line very useful for human risk evaluation. The seasonal variability of the physical–chemical water characteristics (AOX, UV 254 nm, potential formation of THM, pH and temperature) made indispensable experimentation with water samples taken during the various seasons. Autumn waters cause greater toxicity compared to those of other seasons, in particular dilution of the concentrate at 0.5 l equivalent of disinfected waters with chlorine dioxide and peracetic acid causes a 55% reduction in cellular vitality while the cellular vitality is over 80% with the all other water concentrates. Moreover it is very interesting underline that non-cytotoxic quantities of the autumnal water concentrates cause, after 2 h treatment, a decrease in GSH and a statistically significant increase in oxygen radicals, while after prolonged treatment (24 h) cause a GSH increase, without variations in the oxygen radical content. This phenomenon could be interpreted as the cellular adaptation response to an initial oxidative stress.

Development of Human Risk Evaluation System of Household Chemical Products Based on Consumers' View Points

Development of Human Risk Evaluation System of Household Chemical Products Based on Consumers' View Points

Hierarchization of animal teratology findings for improving the human risk evaluation of drugs

The risk assessment of drugs in pregnancy can be improved through better knowledge and interpretation of significant experimental findings. Embryo–fetal effects can be considered as the endpoint of importance, after excluding that their occurrence is related to maternal toxicity. If embryo–fetal toxic effects occur in the presence of maternal toxicity, the dam influence should be clearly assessed, and can be taken into account in the determination of a safety margin. A determination of the lowest developmental toxic dose, if any, apart from any maternal toxicity, should be made. With positive animal developmental findings, interpretation should take into account various parameters including the incidence and the severity of the embryo–fetal insult, interspecies reproducibility, the level of exposure, metabolic pathways, and the results of possible mechanistic investigations. Hierarchization of the experimental findings should take into account all these parameters together to provide support for the risk assessment in humans.

Urinary Bladder Carcinogenesis

Urinary bladder carcinogenesis in rodents bears numerous similarities to the diseases in humans. In rats, the process progresses through the morphologic stages of simple hyperplasia, papillary and nodular hyperplasia, papilloma, noninvasive, and invasive carcinoma. In mice, the pathogenesis can be similar or can follow a sequence of marked dysplasia with or without hyperplasia, leading to carcinoma in situ and ultimately to high-grade invasive carcinoma. Although the papillary and nonpapillary diseases appear to be related in rodents and in humans, they are distinct morphologically, biologically, and molecularly. Numerous classes of genotoxic chemicals have been identified as bladder carcinogens in rodents, and some of these have also been identified as carcinogenic in humans, most notably, aromatic amines, nitrosamines, and cyclophosphamide. In contrast, nongenotoxic chemicals appear to be highly specific with respect to species, strain, diet, agent, dose, and mechanism. For some, it is unclear whether the results at high doses in rodents can be extrapolated to low doses or to humans, e.g., chemicals that cause bladder cancer only at high doses related to the formation of calculi. Numerous observations in rodents can assist in identifying possible mechanisms involved for these nongenotoxic chemicals and therefore can be important for a rational evaluation of human risk.