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Biomedical subjects

L Claudio

Publications and source records attributed to L Claudio.

At least 19 recordsLinked to original sources
PubMed2001

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring. In addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood--brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation). Measurement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure. Physiologically based pharmacokinetic and pharmacodynamic models that incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose--response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic.

Animals↗
PubMed2001

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. II: neuropathology.

Neuropathologic assessment of chemically induced developmental alterations in the nervous system for regulatory purposes is a multifactorial, complex process. This calls for careful qualitative and quantitative morphologic study of numerous brains at several developmental stages in rats. Quantitative evaluation may include such basic methods as determination of brain weight and dimensions as well as the progressively more complex approaches of linear, areal, or stereologic measurement of brain sections. Histologic evaluation employs routine stains (such as hematoxylin and eosin), which can be complemented by a variety of special and immunohistochemical procedures. These brain studies are augmented by morphologic assessment of selected peripheral nervous system structures. Studies of this nature require a high level of technical skill as well as special training on the part of the pathologist. The pathologist should have knowledge of normal microscopic neuroanatomy/neuronal circuitry and an understanding of basic principles of developmental neurobiology, such as familiarity with the patterns of physiologic or programmed cell de

Animals↗
PubMed2000

Testing methods for developmental neurotoxicity of environmental chemicals.

Human brain development is slow and delicate, involving many unique, though interrelated, cellular events. The fetus and child are often more susceptible to chemical toxins that alter the structure and/or function of the brain, although susceptibility varies for individual neurotoxicants. Early exposure to neurotoxins has been implicated in neurological diseases and mental retardation. Pesticide exposures pose a particular concern since many are designed to be neurotoxic to pests and can also affect humans. Acknowledging the potential for vulnerability of the developing brain, EPA recently began to "call in" data on developmental neurotoxicity (DNT) from manufacturers of pesticides already registered and considered to be neurotoxic-around 140 pesticides. Chemicals are to be tested following the DNT testing guideline (OPPTS 870.6300). This paper assesses whether tests performed according to this guideline can effectively identify developmental neurotoxicants. We found the testing guideline deficient in several respects, including: It is not always triggered appropriately within the current tiered system for testing; It does not expose developing animals during all critical periods of vulnerability; It does not assess effects that may become evident later in life; It does not include methodology for consideration of pharmacokinetic variables; Methodology for assessment of neurobehavioral, neuropathological, and morphometry is highly variable; Testing of neurochemical changes is limited and not always required. We propose modifications to the EPA testing guideline that would improve its adequacy for assessing and predicting risks to infants and children. This paper emphasizes that deficiencies in the testing methodology for developmental neurotoxicants represent a significant gap and increase the uncertainty in the establishment of safe levels of exposure to developing individuals.

Animals↗
PubMed2000

Genetic susceptibility to lead poisoning.

Major strides have been taken in the regulation of lead intoxication in the general population, but studies using genetic markers of susceptibility to environmental toxicants raise the question of whether genes can make certain individuals more vulnerable to environmental toxins such as lead. At least three polymorphic genes have been identified that potentially can influence the bioaccumulation and toxicokinetics of lead in humans. The first gene to be discussed in this review is the gene coding for delta-aminolevulinic acid dehydratase (ALAD), an enzyme of heme biosynthesis, that exists in two polymorphic forms. The resulting isozymes have been shown to affect the blood and bone lead levels in human populations. The effects of ALAD in lead intoxication have also been studied in laboratory mice that differ in the genetic dose for this enzyme. The second gene reviewed here is the vitamin D receptor (VDR) gene. The VDR is involved in calcium absorption through the gut and into calcium-rich tissues such as bone. Recent findings suggest that VDR polymorphism may influence the accumulation of lead in bone. Finally, the third gene to be discussed here that may influence the absorption of lead is the hemochromatosis gene coding for the HFE protein. The presence of mutations in the HFE gene leads to hemochromatosis in homozygotic individuals. Because of the associations between iron and lead transport, it is possible that polymorphisms in the HFE gene may also influence the absorption of lead, but this has not yet been studied. More studies will be needed to define the role of these genes in lead intoxication.

Animals↗
PubMed2000

[Risk factors for growth retardation in children of low economic and social level in São Paulo, Brazil].

Aiming to analyze the mild to moderate growth retardation associate factors in children at school age, a case control study was conducted with 153 pairs of seven and eight years old children from public schools of the outskirts of the city. The cases were defined as children with a height for age(H/A) between -1 and -2 Z score, according to NCHS/WHO standards, and matched with a H/A +/- 0.5 Z-score children of same age, gender, school, classroom and class time, as controls. The height was measured at school according to WHO rules by trained professionals, and household visits were carried out to obtain environmental and socio-economic data. Initially the data was analyzed by the univariate conditional method and then, the statistically significant variables were included in a model of multivariate logistic regression analysis. As a result, the risk factors remaining at the end of the multivariate analyses, by Odds Ratio and it's 95% Confidence Interval were respectively:--mother's height: for each decrease of one standard deviation the OR increased 1.84(CI: 1.35 to 2.49); inadequate feeding pattern: OR = 2.12; CI: 1.17 to 3.83, very low socio-economic level: OR = 9.2; CI: 3.35 to 25.13, low birth weight: OR = 2.59; CI: 1.44 to 4.63 and smoking during pregnancy: OR = 1.75; CI: 0.98 to 3.12. These results highlight the environment as a determinant factor for growth performance during the first years of the child's life. Despite this, the significant OR for Mother's height allows the assumption that besides the environment, the parent's height has to be considered as one of the determinants of height deficit, even for the low socioeconomic level.

Body Height↗
PubMed1999

Assessment of the U.S. Environmental Protection Agency methods for identification of hazards to developing organisms, Part I: The reproduction and fertility testing guidelines.

BACKGROUND: Successful reproduction depends on the coordination of many processes, particularly the normal development and subsequent maturation of the sexual organs. The Food Quality Protection Act of 1996 mandates that the U.S. Environmental Protection Agency must protect infants and children from the effects of toxins, including those that affect the reproductive system. Therefore, the Agency finds itself at a critical juncture to make sure that the methods it requires for toxicity testing, the Health Effects Test Guidelines or Series 870 Guidelines, are adequate to determine possible toxicity to children. METHODS AND RESULTS: We found that two testing protocols included in the core guidelines assess toxicological effects on developing animals. This article aims to provide a detailed analysis of the protocols included in the Reproduction and Fertility Effects Test Guideline. An accompanying article assesses the Developmental Toxicity Testing Guideline. We conducted this analysis on the basis of whether the test would yield the information needed to adequately determine risk to infants and children. CONCLUSIONS: Our analysis concludes that given the limitations inherent in testing for reproduction and fertility effects during development, it is necessary to include a safety factor during risk assessment of chemicals. This action will fulfill the mandate expressed in the FQPA to protect infants and children from environmental hazards.

Animals↗
PubMed1999

Assessment of the U.S. Environmental Protection Agency methods for identification of hazards to developing organisms, Part II: The developmental toxicity testing guideline.

BACKGROUND: The effects of toxins on developing animals depend not only on the nature of the chemical but also on the timing of exposure and assessment of outcomes. This complicates the task of regulatory agencies such as the U.S. Environmental Protection Agency (EPA), which must comply with the 1996 Food Quality Protection Act to ensure that their standards and policies protect infants and children from environmental toxins. For this task, the Agency relies heavily on scientific data obtained by manufacturers of industrial chemicals and pesticides following protocols collected under EPA's Health Effects Test Guidelines. METHODS AND RESULTS: This article reviews the protocols included in the EPA guidelines to assess developmental toxicity, which are required for food-use pesticides under the core testing battery. We reviewed these protocols on the basis of their adequacy for identifying hazards to infants and children. Our analysis found limitations in the protocols that hinder their potential for identifying developmental hazards. CONCLUSIONS: Methods that the EPA currently depends upon to identify developmental toxicity of chemicals have limitations that impede obtaining complete and reliable data on which to base regulatory decisions that protect children. Other methodological approaches need to be explored as alternatives or supplements to the current protocols. Until more accurate testing protocols become available, it may well be necessary under existing laws to employ safety factors that are more protective of the health of children at all stages of development.

Animals↗
PubMed1999

Lead acetate exposure inhibits nitric oxide synthase activity in capillary and synaptosomal fractions of mouse brain.

The toxicity of lead (Pb) is of concern to public health due to its persistence in the environment. Brain is one of the major target organs where severe neurologic alterations may be triggered after exposure. The primary effects of lead on brain functions are thought to be a damage to the nervous system microvasculature. However, the mechanism of this toxicity is poorly understood. Nitric oxide synthase (NOS) may be a target for lead and changes in its function can result in a cascade of pathophysiological effects that may be observed in isolated capillaries and synaptosomes. We have determined the concentration of lead in blood, capillaries and synaptosomes in brain from mice receiving 0, 250, 500, and 1000 ppm of lead for 14 days, through the drinking water. NOS activity was determined in the capillaries and synaptosomes by following the conversion of 3H-L-arginine to 3H-L-citrulline. The results show that blood lead levels were dose-dependent. Brain capillaries showed a preferential accumulation of lead as compared to synaptosomes. With all Pb treatments, synaptosomal constitutive NOS was inhibited (about 50% of control) while the inducible NOS activity in capillaries was enhanced. These data suggest that inhibition of cNOS activity and increase in iNOS may contribute to the Pb effects on the CNS.

Animals↗
PubMed1999

The challenge for Cuba.

The restrictions of a U.S. trade embargo and the collapse of the Soviet Union marked the beginning of a period of extreme economic hardship in Cuba. Economic adversity has had tremendous effects, both positive and negative, on all aspects of life on the Island, including environmental and public health.

Cuba↗
PubMed1999

Pesticides and inner-city children: exposures, risks, and prevention.

Six million children live in poverty in America's inner cities. These children are at high risk of exposure to pesticides that are used extensively in urban schools, homes, and day-care centers for control of roaches, rats, and other vermin. The organophosphate insecticide chlorpyrifos and certain pyrethroids are the registered pesticides most heavily applied in cities. Illegal street pesticides are also in use, including tres pasitos (a carbamate), tiza china, and methyl parathion. In New York State in 1997, the heaviest use of pesticides in all counties statewide was in the urban boroughs of Manhattan and Brooklyn. Children are highly vulnerable to pesticides. Because of their play close to the ground, their hand-to-mouth behavior, and their unique dietary patterns, children absorb more pesticides from their environment than adults. The long persistence of semivolatile pesticides such as chlorpyrifos on rugs, furniture, stuffed toys, and other absorbent surfaces within closed apartments further enhances urban children's exposures. Compounding these risks of heavy exposures are children's decreased ability to detoxify and excrete pesticides and the rapid growth, development, and differentiation of their vital organ systems. These developmental immaturities create early windows of great vulnerability. Recent experimental data suggest, for example, that chlorpyrifos may be a developmental neurotoxicant and that exposure in utero may cause biochemical and functional aberrations in fetal neurons as well as deficits in the number of neurons. Certain pyrethroids exert hormonal activity that may alter early neurologic and reproductive development. Assays currently used for assessment of the toxicity of pesticides are insensitive and cannot accurately predict effects to children exposed in utero or in early postnatal life. Protection of American children, and particularly of inner-city children, against the developmental hazards of pesticides requires a comprehensive strategy that monitors patterns of pesticide use on a continuing basis, assesses children's actual exposures to pesticides, uses state-of-the-art developmental toxicity testing, and establishes societal targets for reduction of pesticide use.

Adult↗
PubMed1999

Socioeconomic factors and asthma hospitalization rates in New York City.

Asthma morbidity and mortality are not distributed homogeneously among populations. To assess the relationship between asthma hospitalization rates and socioeconomic factors, we conducted an ecologic analysis using small geographical areas defined by postal zip code in New York City. Asthma hospitalization rates correlated with low median family income, percentage of minorities in the population, and percentage of children under the age of 18. Lack of access to preventive health care, poor housing conditions, environmental exposures, and genetic susceptibility may contribute to high incidence of asthma in some neighborhoods. This report supports the role of socioeconomic factors in asthma and serves to provide data for regulatory and health agencies to concentrate their efforts on neighborhoods most in need.

Adolescent↗
PubMed1998

Environmental health sciences education--a tool for achieving environmental equity and protecting children.

Children are highly susceptible to deleterious effects of environmental toxins. Those who live in underserved communities may be particularly at risk because environmental pollution has been found to be disproportionately distributed among communities. Mounting evidence suggests that asthma rates are rising and that this disease can be caused or aggravated by air pollution. Although ambient air quality has generally improved, these improvements have not reached minority communities in equal proportions. This and other data has fueled the concept of environmental justice or environmental equity, which has led to community activism and government actions. One possible example of environmental inequity and its consequences is the Hunt's Point community, in the South Bronx, New York. This community experiences a high pollution burden with the siting of facilities that emit hazardous wastes into the air. Our approach to this problem has been the formation of mechanisms for bidirectional communication between community residents, government entities, and academic institutions such as Mount Sinai Medical Center. As a result of this experience, we believe that the key to achieving environmental health, especially in communities of color where many children are at risk, is to empower residents to take charge of their environment by providing relevant educational opportunities. Strategies for environmental health education include multitiered training approaches that include community residents, parent education, direct children education, and community education through professional counselors and train-the-trainer approaches. We propose that academic researchers must use community residents not just as subjects of our studies, but to increase our mutual understanding of environmental health, resulting in active participation of community members in research design, data collection, analysis, and dissemination of results in order to make intervention strategies more effective.

Child↗
PubMed1997

A murine model of genetic susceptibility to lead bioaccumulation.

Previous reports have shown that blood lead levels in humans are associated with a polymorphic form of delta-aminolevulinate dehydratase (ALAD), an enzyme of heme biosynthesis that binds and is inhibited by lead. We hypothesized that ALAD levels may influence the distribution and accumulation of lead in the blood and target organs. To assess this, we studied strains of mice that differ in the numbers of copies of the ALAD gene. Our findings showed that mice with a duplication of the ALAD gene (DBA) accumulated twice the amount of lead in their blood and had higher lead levels in kidney and liver than mice with a single copy of the gene (C57) exposed to the same oral doses of lead during adulthood. Hybrid animals showed intermediate blood lead levels. Levels of blood zinc protoporphyrin (ZPP) increased with lead exposure in C57 animals while they were not affected in DBA mice, suggesting protection from production of this abnormal enzyme in mice with a duplication of the gene. Except for these protective effects in the formation of ZPP in DBA animals, duplication of the ALAD gene was found to increase lead accumulation. We conclude that although these mouse strains do not precisely replicate the polymorphism observed in humans, they may be used as a model to study genetic influences in lead bioaccumulation. Understanding genetic factors that affect susceptibility to lead-induced intoxication could have important implications for public health and intervention initiatives. These mouse strains may represent a useful model for future study of the role of ALAD in lead intoxication.

Administration, Oral↗