Biomonitoring of Human Fetal Exposure to Environmental Chemicals in Early Pregnancy

The first trimester of human fetal life, a period of extremely rapid development of physiological systems, represents the most rapid growth phase in human life. Interference in the establishment of organ systems may result in abnormal development that may be manifest immediately or programmed for later abnormal function. Exposure to environmental chemicals may be affecting development at these early stages, and yet there is limited knowledge of the quantities and identities of the chemicals to which the fetus is exposed during early pregnancy. Clearly, opportunities for assessing fetal chemical exposure directly are extremely limited. Hence, this review describes indirect means of assessing fetal exposure in early pregnancy to chemicals that are considered disrupters of development. Consideration is given to such matrices as maternal hair, fingernails, urine, saliva, sweat, breast milk, amniotic fluid and blood, and fetal matrices such as cord blood, cord tissue, meconium, placenta, and fetal liver. More than 150 articles that presented data from chemical analysis of human maternal and fetal tissues and fluids were reviewed. Priority was given to articles where chemical analysis was conducted in more than one matrix. Where correlations between maternal and fetal matrices were determined, these articles were included and are highlighted, as these may provide the basis for future investigations of early fetal exposure. The determination of fetal chemical exposure, at the time of rapid human growth and development, will greatly assist regulatory agencies in risk assessments and establishment of advisories for risk management concerning environmental chemicals.     

A New Method for Estimating Dermal Absorption from Chemical Exposure. 1. General Approach

To evaluate systemic chemical exposure from dermal absorption, one must know the mass of chemical absorbed including the portion that has entered the skin but not yet entered the body's interior system. Algebraic equations are presented for estimating dermal absorption including the effects of exposure time and chemical nature of the compound, in particular lipophilicity and molecular weight. The proposed equations account for larger absorption rates during the initial exposure period as well as the hydrophilic barrier which the viable epidermis presents to lipophilic chemicals. These algebraic expressions are shown to represent adequately the exact solution of the unsteady-state diffusion equations for a two-membrane composite. Finally, procedures are proposed for estimating a priori the required physicochemical data when experimental values are not available. Specifically, the Potts and Guy permeability correlation is split into parts separately representing stratum corneum partitioning and diffusivity.     

The Importance of Delivered Dose in Estimating Low-Dose Cancer Risk from Inhalation Exposure to Formaldehyde

The Importance of Delivered Dose in Estimating Low-Dose CancerRisk from Inhalation Exposure to Formaldehyde. STARR, T. B.,AND BUCK, R. D. (1984). Fundam, AppL Toxicol. 4, 740–753.Data have recently been obtained on the concentration of formaldehydecovalently bound to the respiratory mucosal DNA of Fischer-344rats following two 6-hr inhalation exposures to gaseous formaldehyde.These data provide a direct short-term measure of the deliveredformaldehyde dose in target tissue as a function of the formaldehydeconcentration in ambient air. They also demonstrate that thedelivered dose/administered dose relationship is significantlynonlinear. Since chronic inhalation exposure of Fischer-344rats to high concentrations of gaseous formaldehyde inducessquamous cell carcinomas of the nasal cavity, and since widespreadconcern exists that formaldehyde exposure may also pose a cancerrisk for humans, the implications of this nonlinearity for low-doserisk extrapolation were investigated. The incidence of nasalsquamous cell carcinomas in a chronic formaldehyde inhalationbioassay was reanalyzed with several low-dose extrapolationmodels, using the estimated concentration of formaldehyde covalentlybound to respiratory mucosal DNA as the measure of exposure.For this purpose, it was assumed that the short-term observationsof covalent binding were representative of steady-state conditionsduring the course of the chronic study and further, that thecovalent binding of formaldehyde to target tissue DNA is animportant factor in nasal tumor induction. Resulting maximumlikelihood risk estimates and upper 95% confidence bounds wereunilaterally lower than the corresponding risk measures basedon administered dose, irrespective of the dose-response modelemployed. Reductions in estimated risk ranged from a factorof 2.5, for the multistage model upper 95% confidence bound,to over 10 orders of magnitude, for the probit model upper 95%confidence bound. These results indicate that the concept ofdelivered dose can have a significant impact on estimates oflow-dose risk and should therefore at least be considered asan alternative dose measure in assessments of human cancer riskfrom formaldehyde exposure     

The Use of Arbitrarily Primed PCR (AP-PCR) Fingerprinting to Detect Exposure to Genotoxic Chemicals

Exposure of an organism to a genotoxic chemical may result in the formation of covalently bound adducts between the chemical (or its metabolites) and the DNA; faulty repair of these adducts often results in mutations and, sometimes, cytogenetic changes. The primary effects of such exposure (i.e. adduct formation) and the subsequent effects on the DNA (mutation, cytogenetic damage) may be monitored using a number of assays of varying sensitivity and specificity. Recent developments in molecular biology offer new possibilities for detecting DNA damage. In this laboratory DNA fingerprinting by arbitrarily primed polymerase chain reaction (AP-PCR) was investigated in order to establish whether it can reveal differences in the DNA fingerprints of animals exposed to benzo[a]pyrene in the laboratory and of animals from control and from polluted areas. The results indicate that differences between control and exposed animals were detectable; these results, together with those from other laboratories, indicate that DNA fingerprinting by AP-PCR offers a useful alternative biomarker assay for the detection of the genotoxic effects of environmental pollutants. This paper reviews the application of PCR based DNA fingerprinting procedures in mutation detection and discusses their application to ecotoxicological studies.     

Dynamic Inhalation System for Individual Whole-Body Exposure of Mice to Volatile Organic Chemicals

Abstract

The in vivo rate of metabolism of gases and vapors can be quantitated from the uptake of a chemical by animals exposed in either a closed inhalation system or a dynamic inhalation system. Chemicals that are highly extracted by the animal due to solubility are best studied in a dynamic inhalation system, where the rate of metabolism is quantitated from the steady-state uptake of the chemical. A physiologically based pharmacokinetic model was used to design a dynamic inhalation system for exposing individual male B6C3F1 mice to butadiene and styrene. The system volume and flow rate were identified as important system parameters for using the dynamic system to quantitate the rate of metabolism. The constructed system had a total volume of 0.324 L and was operated at an overall flow rate of 0.97 L/h. The small volume and low flow rate maximized the difference between the inlet and outlet concentration of the chemicals when a mouse was present in the inhalation system. Because of the low overall flow rate through the system, a recirculating line was added to the chamber to ensure the atmosphere in the chamber was well mixed and to remove CO₂ from the chamber. Use of the recirculation line is analogous to placing a fan in the chamber. The recirculating flow was 5 L/h. Estimates of intraspecies variability in the rate of metabolism were made from repetition of individual exposures. The mice were unrestrained in the exposure system to prevent restraint stress from affecting their metabolism or physiology. The dynamic inhalation system can be adapted to expose larger rodents or converted to a closed system for uptake studies with appropriate gases and vapors.     

A Machine Learning Approach to Predict Interdose Vancomycin Exposure

Pharmaceutical Research - Estimation of vancomycin area under the curve (AUC) is challenging in the case of discontinuous administration. Machine learning approaches are increasingly used and can...     

Fluctuating Asymmetry and Growth as Biomarkers for Exposure to Androgen Disrupting Chemicals in Japanese Quail

The effects of embryonic exposure to androgen disrupting chemicals (ADCs) on growth and fluctuating asymmetry (FA) were determined in Japanese quail chicks. Embryos were exposed to an anti-androgenic chemical, 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (p,p′-DDE) at 20 or 40 μg , or to an androgenic chemical, trenbolone acetate, at 5 or 50 μg on day one of incubation. Growth was measured by body weight and tarsus and culmen lengths from day of hatch until day 29. FA was measured as differences in right versus left lengths of the tarsus, radius, zygomatic process, and premaxilla in day old carcasses. No differences in FA were observed for either treatment. Embryonic exposure to DDE resulted in no significant differences in all measures of growth, although the same quail exhibited significant differences in immunological, reproductive, and behavioral measurements (reported elsewhere). Chicks exposed to trenbolone exhibited no differences in body weight or measures of FA at day of hatch, however, subsequent growth was inhibited. This study shows that although growth and FA are often used as measures of chemical stress experienced during embryonic development, they are not sensitive measures for exposure to these ADCs at these levels in Japanese quail.     

Foetal Exposure to Food and Environmental Carcinogens in Human Beings

Abstract: Exposure to many different chemicals during pregnancy through maternal circulation is possible. Transplacental transfer of xenobiotics can be demonstrated using human placental perfusion. Also, placental perfusion can give information about the placental kinetics as well as metabolism and accumulation in the placenta because it retains the tissue structure and function. Although human placental perfusion has been used extensively to study the transplacental transfer of drugs, the information on food and environmental carcinogens is much more limited. This review deals with the foetal exposure to food and environmental carcinogens in human beings. In particular, human transplacental transfer of the food carcinogens such as acrylamide, glycidamide and nitrosodimethylamine are in focus. Because these carcinogens are genotoxic, the functional capacity of human placenta to induce DNA adduct formation or metabolize these above mentioned CYP2E1 substrates is of interest in this context.     

Environmental Chemicals: From the Environment to Food,to Breast Milk,to the Infant

Food is a source of exposure to many environmental chemicals found in human milk and other biological specimens. Ingestion of foods containing high amounts of animal fat is the main route of human exposure to lipophilic chemicals, such as persistent organic pollutants, which tend to bioaccumulate in the lipid compartment. Bioaccumulation results in increased exposure of these chemicals for humans, but particularly to breastfeeding infants, who are at the top of the food chain. The extent to which food contributes to a person's overall exposure depends on individual dietary habits and the concentrations of chemical residues in the food. These, in turn, are affected by (1) application methods, (2) properties and amounts of the chemical, and (3) preparation, handling, and the properties of the food. Once the food is ingested by the lactating woman, the chemical's pharmacokinetics and the transport mechanisms producing the movement of solutes across mammary alveolar cells determine the passage of chemicals from the blood to the milk. Thus, several factors affect the presence in human milk of environmental chemicals from dietary sources.     

Estimating the Exposure of Birds and Mammals to Pesticides in Long-term Risk Assessments

This paper reviews current EU pesticide risk assessment guidance [European Commission (2002) Guidance document on risk assessment for birds and mammals under council directive 91/414/EEC, SANCO/4145/2000EC 2002], and examines some of its assumptions and problems arising from them. Issues associated with obtaining data that adequately describes exposure over the appropriate time-scale are common to both acute and long-term risk assessments but are probably less problematic for long-term exposure. Improvements in problem formulation and ways in which temporal and spatial factors might be incorporated into long-term risk assessments are suggested. The most important temporal issue for long-term risk is how best to model the degree to which wildlife habits are predictable from day to day. In relation to spatial factors, it is suggested that long-term risk assessments could make better use of pesticide usage data that sample usage patterns throughout the UK. The usefulness of detailed simulated farming landscapes populated by wildlife represented as agent-based models, should be explored.     

Health Effects of Subchronic Exposure to Environmental Levels of Diesel Exhaust

Diesel exhaust is a public health concern and contributor to both ambient and occupational air pollution. As part of a general health assessment of multiple anthropogenic source emissions conducted by the National Environmental Respiratory Center (NERC), a series of health assays was conducted on rats and mice exposed to environmentally relevant levels of diesel exhaust. This article summarizes the study design and exposures, and reports findings on several general indicators of toxicity and carcinogenic potential. Diesel exhaust was generated from a commonly used 2000 model 5.9-L, 6-cylinder turbo diesel engine operated on a variable-load heavy-duty test cycle burning national average certification fuel. Animals were exposed to clean air (control) or four dilutions of whole emissions based on particulate matter concentration (30, 100, 300, and 1000 μg/m³). Male and female F344 rats and A/J mice were exposed by whole-body inhalation 6 h/day, 7 days/wk, for either 1 wk or 6 mo. Exposures were characterized in detail. Effects of exposure on clinical observations, body and organ weights, serum chemistry, hematology, histopathology, bronchoalveolar lavage, and serum clotting factors were mild. Significant exposure-related effects occurring in both male and female rats included decreases in serum cholesterol and clotting Factor VII and slight increases in serum gamma-glutamyl transferase. Several other responses met screening criteria for significant exposure effects but were not consistent between genders or exposure times and were not corroborated by related parameters. Carcinogenic potential as determined by micronucleated reticulocyte counts and proliferation of adenomas in A/J mice were unaffected by 6 mo of exposure. Parallel studies demonstrated effects on cardiac function and resistance to viral infection; however, the results reported here show few and only modest health hazards from subchronic or shorter exposures to realistic concentrations of contemporary diesel emissions.     

Health Effects of Subchronic Exposure to Environmental Levels of Hardwood Smoke

Hardwood smoke is a contributor to both ambient and indoor air pollution. As part of a general health assessment of multiple anthropogenic source emissions conducted by the National Environmental Respiratory Center, a series of health assays was conducted on rodents exposed to environmentally relevant levels of hardwood smoke. This article summarizes the study design and exposures, and reports findings on general indicators of toxicity, bacterial clearance, cardiac function, and carcinogenic potential. Hardwood smoke was generated from an uncertified wood stove, burning wood of mixed oak species. Animals were exposed to clean air (control) or dilutions of whole emissions based on particulate (30, 100, 300, and 1000 μm g/m³). F344 rats, SHR rats, strain A/J mice, and C57BL/6 mice were exposed by whole-body inhalation 6 h/day, 7 days/wk, for either 1 wk or 6 mo. Effects of exposure on general indicators of toxicity, bacterial clearance, cardiac function, and carcinogenic potential were mild. Exposure-related effects included increases in platelets and decreases in blood urea nitrogen and serum alanine aminotransferase. Several other responses met screening criteria for significant exposure effects but were not consistent between genders or exposure times and were not corroborated by related parameters. Pulmonary histopathology revealed very little accumulation of hardwood smoke particulate matter. Parallel studies demonstrated mild exposure effects on bronchoalveolar lavage parameters and in a mouse model of asthma. In summary, the results reported here show few and only modest health hazards from short-term to subchronic exposures to realistic concentrations of hardwood smoke.     

Neonatal Exposure to Endocrine Disrupting Chemicals Impairs Learning Behaviour by Disrupting Hippocampal Organization in Male Swiss Albino Mice

Hippocampus is highly susceptible to endocrine disrupting chemicals exposure particularly during the critical phase of brain development. In this study, mice offspring were exposed to endocrine disruptors mancozeb (MCZ) and imidacloprid (IMI) individually (40 mg MCZ and 0.65 mg IMI/kg/day) as well as to their equimixture (40 mg MCZ + 0.65 mg IMI/kg/day) through the diet of lactating mothers from post‐natal day (PND) 1 to PND 28. Half of the randomly selected male offspring were killed at PND 29, and the rest half were left unexposed and killed at PND 63. Brain weight, histology, plasma hormone profile and working memory performance were the various end‐points studied. Brain weight was significantly decreased in the mixture‐exposed group at PND 29, which persisted to PND 63. Total thickness of pyramidal cell layers decreased significantly along with misalignment, shrinkage and degeneration of pyramidal neurons in CA1 and CA3 regions of the IMI and mixture‐exposed groups. The length and branch points of dendrites of pyramidal neurons were decreased significantly in mixture‐exposed group at both PND 29 and PND 63. Dendritic spine density was also reduced in mixture‐exposed group offspring. Testosterone level was significantly decreased only at PND 29, but corticosterone level was increased at both PND 29 and PND 63 in mixture‐exposed offspring. T‐maze task performance revealed significantly increased time duration and reduced path efficiency in mixture‐exposed group offspring. The results thus indicate that pesticide mixture exposure could lead to changes in learning behaviour even at doses that individually did not induce any adverse effect on hippocampal organization.     

Environmental Exposure to Methylmercury is Associated with a Decrease in Nitric Oxide Production

Abstract: Some studies have recently suggested that mercury (Hg)‐exposed populations face increased risks of cardiovascular diseases, and experimental data indicate that such risks might be due to reductions in nitric oxide bioavailability. However, no previous study has examined whether Hg exposure affects plasma nitrite concentrations in humans as an indication of nitric oxide production. Here, we investigated whether there is an association between circulating nitrite and Hg concentrations in whole blood, plasma and hair from an exposed methylmercury (MeHg) population. Hair and blood samples were collected from 238 persons exposed to MeHg from fish consumption. Hg concentrations in plasma (PHg), whole blood (BHg) and hair Hg (HHg) were determined by inductively coupled plasma‐mass spectrometry. Mean BHg content was 49.8 ± 35.2 μg/l, mean PHg was 7.8 ± 6.9 μg/l and HHg 14.6 ± 10.6 μg/g. Mean plasma nitrite concentration was 253.2 ± 105.5 nM. No association was found between plasma nitrite concentration and BHg or HHg concentrations in a univariate model. However, multiple regression models adjusted for gender, age and fish consumption showed a significant association between plasma nitrite and plasma Hg concentration (β = ?0.1, p < 0.001). Our findings constitute preliminary clinical evidence that exposure to MeHg may cause inhibitory effects on the production of endothelial nitric oxide.     

Assessment of Human Exposure to Five Alternaria Mycotoxins in China by Biomonitoring Approach

This biomonitoring study was conducted to investigate the concentration levels of five Alternaria mycotoxins in urine samples from 269 healthy volunteers living in the Yangtze River Delta, China. Alternariol (AOH), alternariol monomethyl ether (AME), tenuazonic acid (TeA) and tentoxin (TEN) were detected in 38.3%, 48.7%, 63.9% and 23.4% of urine samples with the concentrations ranging from 0.057 to 45.8 ng/mL, 0.020 to 0.802 ng/mL, 0.050 to 80.6 ng/mL and 0.021 to 0.939 ng/mL, respectively. Altenuene (ALT) was not detected in any urine sample. Based on the urinary concentrations, the probable daily intake (PDI) values of Alternaria mycotoxins were calculated, and 100%, 99.2–100%, 0.372% and 1.12% of participants exceeded the threshold of toxicological concern (TTC) values for AOH, AME, TeA and TEN, respectively. This study revealed high potential health risks related to the contaminations of major Alternaria mycotoxins in China and highlighted the necessity for more toxicological studies to provide better basis for further comprehensive risk assessments.     

The Council for Health and Environmental Safety of Soils.

The Council for Health and Environmental Safety of Soils (CHESS) was organized in 1987 to develop a consensus soil risk assessment methodology to be used as a framework for establishing standards for soil contamination to protect the environment and public health. The wide range of contaminating substances of possible health concern in soil is affecting land use and development, causing excessive economic expenditures, and the regulatory approaches for control are disperse. The International Society of Regulatory Toxicology and Pharmacology agreed to sponsor the Council and through a Governing Board composed of experienced scientists from the federal government, state departments of public health and environmental protection, academia, and the private sector including industry and environmental organizations. The Board was created to support the goals of CHESS, its mode of operation, and to establish funding policies and directions. A technical council agreed to develop a peer-reviewed consensus methodology to assess public health risks from contaminated soil by technical committees composed of recognized experts in the area of soil contamination and other relevant disciplines. This methodology would then be made available to federal and state agencies, the private sector, and the scientific community at large. After extensive study, a final decision was made to develop a decision-tree framework to be used at the state and local levels for application to all types of soil contamination. Following extensive studies it was agreed the ubiquitous nature of petroleum contamination in soil has direct and immediate public health implications and CHESS therefore directed its first efforts to this area.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exposure of Adult Mice to Environmental Tobacco Smoke Fails to Enhance the Immune Response to Inhaled Antigen

Epidemiologic evidence supports a role for environmental tobacco smoke (ETS) in the occurrence and severity of allergies/asthma. However, neither the precise combination of ETS and allergen exposure nor the mechanism (or mechanisms) by which these factors interact and contribute to asthma induction is known. Animal model studies have failed to establish a convincing relationship between ETS exposure and asthma induction, perhaps because of methodological inadequacies. Here, we tested the hypothesis that ETS inhalation would provoke an asthmatic response by overcoming normal airway tolerance to inhaled antigens. Our protocol combined daily ETS exposure with nose-only sensitization to ovalbumin. Three strains of mice were tested, each with a different level of susceptibility to airway hypersensitivity. Immunological responses were assessed by immunoglobulin production. Airway inflammation was assessed by bronchoalveolar lavage differentials and lung histopathology. Airway hyperresponsiveness was determined by methacholine challenge. The mice produced ovalbumin-specific antibodies following ovalbumin exposure in a strain-dependent manner. Only the A/J mice produced detectable levels of ovalbumin-specific immunoglobulin (Ig) E. Both A/J and BALB/c mice produced ovalbumin-specific IgG1 antibodies. The C57Bl/6 mice did not produce detectable levels of antibodies. The A/J mice also exhibited airway inflammation following ovalbumin exposure. Neither the C57Bl/6 nor the BALB/c mice exhibited signs of airway inflammation. Exposure to ETS failed to enhance ovalbumin-specific antibody production, airway inflammation, or hyperresponsiveness. Together these results indicate that ETS exposure accompanied by nose-only allergen sensitization fails to overcome aerosol tolerance in adult mice.