Toxicology and human health effects following exposure to oxygenated or reformulated gasoline.

In order to replace antiknock leaded derivatives in gasoline, legislations were enacted in the United States and other countries to find safer additives and to reduce CO, O3, and volatile organic compounds (VOCs) in non-attainment areas. Oxygenates commonly used include various alcohols and aliphatic ethers. Methyl tert-butyl ether (MTBE) is the most widely used and studied ether oxygenate and is added to gasoline at concentrations up to 15% by volume. Inhalation of fumes while fueling automobiles is the main source of human exposure to MTBE. Humans are also exposed when drinking water contaminated with MTBE. Epidemiological, clinical, animal, metabolic and kinetic studies have been carried out to address human health risks resulting from exposure to MTBE. MTBE is an animal carcinogen, but its human carcinogenic potential remains unclear. Because MTBE functions as a non-traditional genotoxicant, several mechanisms were suggested to explain its mode of action, such as, functioning as a cytotoxic as opposed to a mitogenic agent; involvement of hormonal mechanisms; or operating as a promoter instead of being a complete carcinogen. Some studies suggested that carcinogenicity of MTBE might be due to its two main metabolites, formaldehyde or tributanol. A role for DNA repair in MTBE carcinogenesis was recently unveiled, which explains some, but not all effects. The totality of the evidence shows that, for the majority of the non-occupationally exposed human population, MTBE is unlikely to produce lasting adverse health effects, and may in some cases improve health by reducing the composition of emitted harmful VOCs and other substances. A small segment of the population (e.g. asthmatic children, the elderly, and those with immunodeficiency) may be at increased risk for toxicity. However, no studies have been conducted to investigate this hypothesis. Concern over ground and surface water contamination caused by persistent MTBE has lead the Environmental Protection Agency (EPA) to proposed reducing or eliminating its use as a gasoline additive. The major potential alternatives to MTBE are other forms of ethers such as ethyl tert-butyl ether (ETBE) or tert-amyl methyl ether (TAME), and alcohols such as ethanol. More definitive studies are needed to understand the mechanism(s) by which aliphatic ethers may pose health and environmental impacts. The switch from MTBE to ethanol is not without problems. Ethanol costs more to produce, poses challenges to the gasoline distribution system, extends the spread of hydrocarbons through ground water in gasoline plumes, and in the short-term is unlikely to be available in sufficient quantity. Moreover, its metabolite acetaldehyde is a possible carcinogen that undergoes a photochemical reaction in the atmosphere to produce the respiratory irritant peroxylacetate nitrate (PAN). Congress is addressing whether the Clean Air Act Amendments (CAA) provisions concerning reformulated gasoline (RFG) should be modified to allow refineries to discontinue or lessen the use of oxygenates.

Hereditary spastic paraplegia and Evans's syndrome.

Two brothers with hereditary spastic paraplegia and Evans's syndrome are recorded. Rapid deterioration of functional motor ability followed the development of Evans's syndrome.

Pyogenic sacroiliitis in children: Diagnostic dilemma and management.

Pyogenic sacroiliitis is a relatively rare condition in children. Vigilance and careful clinical examination of the joint could minimize the delay in diagnosis. In areas endemic for brucellosis, negative serology, raised erythrocyte sedimentation rate, positive magnetic resonance imaging, isotope bone scan and bacteriological culture confirm diagnosis. Appropriate adequate antibiotic therapy for four to six weeks cures the infection and prevents morbidity.

Toxicological effects of ethanol on human health.

Moderate ethanol consumption reduces stress and increases feelings of happiness and well-being, and may reduce the risk of coronary heart disease. Heavy consumption of alcohol, however, may cause addiction and increases all types of injury and trauma. Environmental and genetic factors are involved in susceptibility to alcoholism. Ethanol can lead to malnutrition, and can exert a direct toxicological effect due to its interference with hepatic metabolism and immunological functions. A causal effect has been observed between alcohol and various cancers. Cessation of alcohol consumption and balanced nutrition are recommended primary nonspecific therapeutic measures for alcoholics. Drug therapies for alcoholics suffering from liver injury has resulted in mixed results. In end-stage liver disease, liver transplantation may be considered.

Risk assessment and management of chemical contaminants in fishery products consumed in the USA.

In the USA a small proportion of fishery products are contaminated with appreciable amounts of potentially hazardous contaminants. However, risks to consumers are not generally high. Inorganic contaminants with the greatest potential for toxicity are antimony, arsenic, cadmium, lead, mercury, selenium and sulfites. Among organic compounds, polychlorinated biphenyls, dioxins, several chlorinated hydrocarbon insecticides, certain processing-related and aquaculture-related contaminants pose potential risks for consumers. Log-normal distributions appear to provide good descriptions of the pattern of variation of contaminant concentrations among different geographic areas, and some contaminants (mostly organic) appear to be much more variable than others. This variability offers a solution for reduction of exposure through restricting the harvest of aquatic organisms from specific sites, and by excluding certain species. It is recommended that: (i) existing State and Federal regulations and environmental monitoring be strengthened and enforced to minimize contamination of the aquatic environment; (ii) a program of shared responsibility be instituted, where Federal agencies develop a set of monitoring and inspection practices and state agencies assume responsibility for primary control, site closures and advisories issue; (iii) research and public education by government agencies and health professionals be expanded to determine actual risks and approaches to manage them; (iv) mandatory labeling be considered for specific contaminants; (v) a better system requiring international agreements be developed in order to minimize the differences among various national regulatory approaches.

Human health risks due to consumption of chemically contaminated fishery products.

A small proportion of fishery products contaminated with appreciable amounts of potentially hazardous inorganic and organic contaminants from natural and environmental sources seem to pose the greatest potential for toxicity to consumers of fishery products in the United States. Health risks due to chemicals (e.g., modest changes in the overall risk of cancer, subtle deficits of neurological development in fetuses and children) are difficult to measure directly in people exposed to low levels. Immunocompetence may increase cancer risk. Inferences about the potential magnitude of these problems must be based on the levels of specific chemical present, observations of human populations and experimental animals exposed to relatively high doses, and theories about the likely mechanisms of action of specific intoxicants and the population distribution of sensitivity of human exposure. Lognormal distributions were found to provide good descriptions of the pattern of variation of contaminant concentrations among different species and geographic areas; this variability offers a solution for reduction of exposure through restricting harvest of aquatic animals from certain sites and by excluding certain species. Available information suggest that risks are not generally of high magnitude; nevertheless, their control will significantly improve public health.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultraviolet radiation-induced DNA damage and its photorepair in the skin of the platyfish Xiphophorus.

Fluence response relationships for the induction of DNA damage in the skin of UV-irradiated Xiphophorus fish were obtained by quantitative gel electrophoresis of unlabeled DNA following extraction and treatment with an enzyme preparation that makes single strand breaks next to cyclobutane pyrimidine dimers. A buffer containing 7 M urea minimized the degradation of DNA during extraction and gave reproducible results. The shapes of fluence response curves for the production of dimers by sun lamp irradiation (lambda > 290 nm) or 302 nm in the dermis of grown fish were similar. Photoreversal of dimers was readily observed by black light exposure or from the longer wavelengths (> 304 nm) from sun lamps. As expected, the number of pyrimidine dimers/incident fluence in young fish skin was considerably higher on the irradiated side of immobilized fish than it was in swimming (randomly moving) fish, and the shape of the fluence response curves was linear for all wavelengths used lambda > 290, 302, and 313 nm. On the other hand, young fish irradiated from above with lambda > 290 nm showed a less than linear relationship between pyrimidine dimers in their skin and radiation fluence because most exposure occurred on the dorsal rim of fish skin; thus, some cells in that skin were exposed to high fluences while others were not, leading to a heterogenous population of cells. Values of dimers produced were also much less than in immobilized fish. The pigment melanin decreased the number of dimers in the epidermis of grown fish exposed to lambda > 290, 302, or 313 nm, or in the dermis of fish following 302 nm, thus conferring protection against this kind of damage. No dimers were detected in the epidermis of fish exposed to 365 nm. The dimers produced at 302 and 313 nm at tumoricidal exposures correspond to 1 dimer in 10(5) base pairs.

Urea facilitates quantitative estimation of DNA damage in situ by preventing its degradation.

A buffer containing 7 M urea was used to successfully prevent DNA degradation of in situ damaged fish skin and resulted in reproducible high molecular weight DNA. This treatment in combination with a quantitative gel electrophoresis technique permitted estimation of small changes induced in unlabeled DNA per unit molecular weight after treatment with a DNA damaging agent (e.g., ultraviolet irradiation).

Different rates of ultraviolet-induced DNA damage in the epidermis and dermis of a platyfish model for carcinogenesis.

The purpose of this study was to compare fluence-response relationships for the production of cyclobutane pyrimidine dimers in epidermal or dermal DNA of platyfish Xiphophorus hybrids irradiated with UVB, and to determine photoreactivation from black light on dimers produced in situ. This was accomplished by quantitative gel electrophoresis of unlabeled DNA following extraction of the DNA and treatment with an enzyme specific for the detection of pyrimidine dimers. The dermis was the target tissue for UV-induced DNA damage in Xiphophorus hybrid fish skin. Shapes of dimer-fluence response data following filtered sunlamp irradiation (lambda > 290 nm) or monochromatic wavelength 302 nm in the epidermis or dermis were different. In the epidermis there was an initial step upward slope followed by a plateau, whereas in the dermis a linear relationship was observed. The final values of dimers at the high doses were, however, nearly equal in the epidermis and dermis exposed to either radiation. These differences in fluence-response relationships are probably attributable to the intertwining of the epidermis and to the shielding effect of the epidermal layer, with scales leading to a heterogeneous population of cells which are exposed to different UV doses. Photoreversal of dimers was readily observed by black light irradiation in both epidermis and dermis irradiated with either lambda > 290 nm or 302 nm.

DNA damage, photorepair, and survival in fish and human cells exposed to UV radiation.

The effect of various wavelengths of UVB radiation on the induction of cyclobutane pyrimidine dimers in fish cells and human fibroblasts and the repair of these lesions were studied using an UV-endonuclease to measure dimers (endonuclease sensitive sites) by sedimentation of radioactive DNA, by gel electrophoresis of unlabeled DNA, and by cell survival. The data show that fish cells have an efficient photoreactivation system at wavelength > 304 nm that reverses cytotoxicity and dimer formation after exposure to filtered sunlamp irradiation of a shorter wavelength (lambda > 290 nm). Shorter wavelengths in UVB (> 304 nm) are more effective in photoreversal than longer ones (> 320 nm). As a consequence, 50-85% of dimers induced by these wavelengths in fish are photoreactivated while they are being formed. A major cytotoxicological lesion is the cyclobutane pyrimidine dimers. Cultured human fibroblasts do not possess such a repair system. These results indicate that sunlamp irradiation has wavelengths that both damage and repair DNA.

Effect of nutrition on the health of the elderly.

Nutrition may play a role in the progressive decline of several body functions with aging. Progressive decline in energy, lean body mass, and protein intake are also associated with aging. Many elderly (greater than 55 years old) drink less than the recommended amounts of water and consume less than the Recommended Dietary Allowances of calcium, iron, zinc, copper, thiamin, riboflavin, folate, and vitamins B-12 and D. Nutrition needs of the elderly to maintain activities of daily living are expected to increase in future years. Because diminished physical activity and old age disabilities cause the elderly to modify eating habits acquired at a younger age, dietary and other life-style changes should be implemented early in life so that optimal tissue function will be maintained. More research and development is needed in the areas of nutrient requirements for the elderly, effect of nutrition on chronic diseases, improved methods for assessing nutritional status and screening the elderly for nutritional risk, nutrient-nutrient and nutrient-drug interactions, and educational strategies to provide better nutrition and eliminate health fraud. Dietary interventions show promise, but must be monitored for effectiveness.

Programs of safety surveillance and control of fishery products.

In the United States, fishery product safety at the federal level falls primarily under the authority of the Food and Drug Administration. However, other federal agencies play an important role. The Environmental Protection Agency is responsible for setting and recommending pesticide limits in seafood, and the National Marine Fisheries Service operates a voluntary inspection program. The Centers for Disease Control is responsible for the collection and evaluation of data characterizing the source of seafood-borne illness. Individual states also play a dominant role in the control of seafood-borne risk because of the important differences in consumption and contaminant levels across regions of the country. State public health, environmental protection, and resource management agencies have developed programs designed to mitigate that risk. Because of the complication and variability of the fishery industry, an effective safety system can be developed based on partnership among federal and state agencies, in which state governments retain the dominant role and the federal government develops and updates guidance programs and provides oversight. The international community has developed practices and protocols impacting the regulation of seafood safety in the United States. In view of developing trade agreements, the international community should address the criteria of setting equivalent contaminant levels and consider the option of establishing import contract criteria for fishery products.

Assessment of the carcinogenicity of the nonnutritive sweetener cyclamate.

The weight of the evidence from metabolic studies, short-term tests, animal bioassays, and epidemiological studies indicates that cyclamate (CHS) is not carcinogenic by itself; however, there is evidence from in vitro and in vivo studies in animals that implies it may have cancer-promoting or cocarcinogenic activity. Epidemiological studies indicate that the use of nonnutritive sweeteners (CHS and saccharin) has not resulted in a measurable overall increase in the risk of bladder cancer in individuals who have ever used these products. No epidemiological information exists on the possible associations of these sweeteners and cancers other than those of the urinary tract. It is recommended that (1) no further studies on the metabolism of CHS to evaluate its carcinogenicity are required since no potentially hazardous metabolites have been appreciably detected in humans; (2) no further animal bioassays to test for the carcinogenicity of CHS by itself are necessary; (3) the studies in rodents that suggest a promotional or cocarcinogenic effect of CHS should be repeated because they cannot be ruled out; (4) because the significance to human health of a positive outcome of such studies is uncertain, additional research aimed at understanding the predictive value for human health of such results and more generic studies to develop well-validated systems that can be relied on in the assessment of cancer-promoting agents are recommended; (5) in populations where CHS continues to be used, epidemiological monitoring should be continued to determine whether there is an increased risk of cancer in humans who are heavy or long-term users or for those observed long after first exposure. In such monitoring, other cancer sites--in addition to the bladder--should be considered.

Effect of diet on progression of chronic renal disease.

Changes in renal function induced by protein intake are thought to reflect evolutionary adaptation of the kidney. Excess dietary proteins over long periods may increase normal blood flow and glomerular filtration rate, requiring the continuous use of outer cortex's reserve glomeruli. According to the hyperfiltration theory, pressures and flows in outer cortical glomeruli contribute to continuous intrarenal capillary hypertension and predispose healthy people to progressive glomerular sclerosis and deterioration of renal function. Pressures and flows associated with the response to renal disease in turn may accelerate the development of sclerosis, leading to even more rapid loss of renal function. Restriction of dietary protein (less than or equal to 0.6 g/kg per day) and/or phosphorus seems to slow the rate of loss of renal function in patients with chronic renal insufficiency. Evidence for the role of lipids in the progression of renal disease is not clear. All of these dietary factors possibly play a role in the progression of renal disease; the relative importance of each factor varies, depending on the pathogenesis, stage, and mechanism of progression of the disease. Findings indicate that nutrition therapy can decrease rate of deterioration of renal function in patients with chronic renal diseases.

DNA repair in human fibroblasts treated with a combination of chemicals.

Excision repair of DNA damage was measured by the photolysis of bromodeoxy-uridine incorporated during repair in normal human and xeroderma pigmentosum group C fibroblasts (XP C) treated with a combination of the carcinogens N-acetoxy-2-acetylamino-fluorene (AAAF), and 4-nitroquinoline 1-oxide (4NQO). Repair was additive in normal and XP C cells treated with AAAF plus 4NQO, indicating that there are different rate limiting steps for removal of 4NQO and AAAF lesions.

DNA excision repair in human cells treated with ultraviolet radiation and 7,12-dimethylbenz[a]anthracene 5,6-oxide.

Excision repair was measured in normal human and xeroderma pigmentosum group C cells treated with 7,12-dimethylbenz[a]-anthracene 5,6-oxide and with ultraviolet radiation by the techniques of unscheduled DNA synthesis, repair replication, a modification of bromodeoxyuridine photolysis employing the dye Hoechst 33258 and 365 nm radiation, and endonuclease-sensitive sites assay. Radioautography and repair replication showed that in normal cells the magnitude of repair after a saturation dose of epoxide (approx. 10 microM) to be 0.1-0.2 that after a saturating ultraviolet dose (20 J/m2 at 254), though survival data showed that both doses gave nearly similar killings. Repair was of the long-patch type and repair kinetics after the epoxide treatment were similar to ultraviolet. After a combined treatment with both agents, unscheduled synthesis in normal cells was more than additive, although, considering the experimental errors, these data and those of repair replication are consistent with additivity. The epoxide did not inhibit loss of sites sensitive to the ultraviolet endonuclease. However, after a combined treatment to xeroderma pigmentosum cells there was appreciably less unscheduled synthesis than for the sum of both treatments and the epoxide inhibited the loss of nuclease-sensitive sites. We interpret the data to indicate that there are different rate-limiting steps in the removal of the ultraviolet and the epoxide damages, and that the residual repair activity in xeroderma pigmentosum cells is accomplished by different, not just fewer, enzymes than in normal cells.

The combined action of chemical carcinogens on DNA repair in human cells.

Excision repair was studied in normal human and ataxia telangiectasia (AT) cells proficient in repair of UV and its mimetic chemicals, and in xeroderma pigmentosum group C (XP C) cells (deficient in repair of UV and its mimetics), after treatment with several combinations of chemical carcinogens, by the photolysis of bromodeoxyuridine incorporated into parental DNA during repair. Results indicate that repair was additive in AT, and XP C cells treated with N-acetoxy-2-acetylaminofluorene (AAAF) plus ethyl methanesulfonate (EMS) or methyl methanesulfonate (MMS) indicating that there are different rate limiting steps for removal of both types of damage. Data on the combinations of 4-nitroquinoline 1-oxide (4NQO) plus MMS or EMS are difficult to interpret, but they do not indicate inhibition of DNA repair.