A Systematic Review of Systematic Reviews and Meta-Analyses of Animal Experiments with Guidelines for Reporting

To maximize the findings of animal experiments to inform likely health effects in humans, a thorough review and evaluation of the animal evidence is required. Systematic reviews and, where appropriate, meta-analyses have great potential in facilitating such an evaluation, making efficient use of the animal evidence while minimizing possible sources of bias. The extent to which systematic review and meta-analysis methods have been applied to evaluate animal experiments to inform human health is unknown. Using systematic review methods, we examine the extent and quality of systematic reviews and meta-analyses of in vivo animal experiments carried out to inform human health. We identified 103 articles meeting the inclusion criteria: 57 reported a systematic review, 29 a systematic review and a meta-analysis, and 17 reported a meta-analysis only. The use of these methods to evaluate animal evidence has increased over time. Although the reporting of systematic reviews is of adequate quality, the reporting of meta-analyses is poor. The inadequate reporting of meta-analyses observed here leads to questions on whether the most appropriate methods were used to maximize the use of the animal evidence to inform policy or decision-making. We recommend that guidelines proposed here be used to help improve the reporting of systematic reviews and meta-analyses of animal experiments. Further consideration of the use and methodological quality and reporting of such studies is needed.     

A systematic review of systematic reviews and meta-analyses of animal experiments with guidelines for reporting

To maximize the findings of animal experiments to inform likely health effects in humans, a thorough review and evaluation of the animal evidence is required. Systematic reviews and, where appropriate, meta-analyses have great potential in facilitating such an evaluation, making efficient use of the animal evidence while minimizing possible sources of bias. The extent to which systematic review and meta-analysis methods have been applied to evaluate animal experiments to inform human health is unknown. Using systematic review methods, we examine the extent and quality of systematic reviews and meta-analyses of in vivo animal experiments carried out to inform human health. We identified 103 articles meeting the inclusion criteria: 57 reported a systematic review, 29 a systematic review and a meta-analysis, and 17 reported a meta-analysis only. The use of these methods to evaluate animal evidence has increased over time. Although the reporting of systematic reviews is of adequate quality, the reporting of meta-analyses is poor. The inadequate reporting of meta-analyses observed here leads to questions on whether the most appropriate methods were used to maximize the use of the animal evidence to inform policy or decision-making. We recommend that guidelines proposed here be used to help improve the reporting of systematic reviews and meta-analyses of animal experiments. Further consideration of the use and methodological quality and reporting of such studies is needed.     

A rapid evidence assessment of the potential risk to the environment presented by active ingredients in the UK’s most commonly sold companion animal parasiticides

A number of parasiticides are commercially available as companion animal treatments to protect against parasite infestation and are sold in large volumes. These treatments are not intended to enter the wider environment but may be washed off or excreted by treated animals and have ecotoxic impacts. A systematic literature review was conducted to identify the existing evidence for the toxicity of the six most used parasiticides in the UK: imidacloprid, fipronil, fluralaner, afoxolaner, selamectin, and flumethrin. A total of 17,207 published articles were screened, with 690 included in the final evidence synthesis. All parasiticides displayed higher toxicity towards invertebrates than vertebrates, enabling their use as companion animal treatments. Extensive evidence exists of ecotoxicity for imidacloprid and fipronil, but this focuses on exposure via agricultural use and is not representative of environmental exposure that results from use in companion animal treatments, especially in urban greenspace. Little to no evidence exists for the ecotoxicity of the remaining parasiticides. Despite heavy usage, there is currently insufficient evidence to understand the environmental risk posed by these veterinary treatments and further studies are urgently needed to quantify the levels and characterise the routes of environmental exposure, as well as identifying any resulting environmental harm.

     

Phthalate exposure in pregnant women and their children in central Taiwan

Phthalate exposure was found to be associated with endocrine disruption, respiratory effects, reproductive and developmental toxicity. The intensive use of plastics may be increasing the exposure to phthalates in Taiwanese population, particularly for young children.We studied phthalate metabolites in pregnant women and their newborns in a prospective cohort from a medical center in Central Taiwan. One hundred maternal urine samples and 30 paired cord blood and milk samples were randomly selected from all of participants (430 pregnant women). Eleven phthalate metabolites (MEHP, 5OH-MEHP, 2cx-MEHP, 5cx-MEPP, 5oxo-MEHP, MiBP, MnBP, MBzP, OH-MiNP, oxo-MiNP, and cx-MiNP) representing the exposure to five commonly used phthalates (DEHP, di-isobutyl phthalate (DiBP), DnBP, BBP, DiNP) were measured in urine of pregnant women, cord serum and breast milk after delivery, and in urine of their children. Exposure was estimated with excretion factors and correlation among metabolites of the same parent compound. Thirty and 59 urinary samples from 2 and 5 years-old children were randomly selected from 185 children successfully followed.Total urinary phthalate metabolite concentration (geometric mean, μg L⁻¹) was found to be higher in 2-years-olds (398.6) and 5-years-olds (333.7) than pregnant women (205.2). Metabolites in urine are mainly from DEHP. The proportion of DiNP metabolites was higher in children urine (4.39 and 8.31%, ages 2 and 5) than in adults (0.83%) (p < 0.01). Compared to urinary levels, phthalate metabolite levels are low in cord blood (37.45) and milk (14.90). DEHP metabolite levels in women’s urine and their corresponding cord blood are significantly correlated. Compared to other populations in the world, DEHP derived metabolites in maternal urine were higher, while phthalate metabolite levels in milk and cord blood were similar. The level of phthalate metabolites in milk and cord blood were comparable to those found in other populations. Further studies of health effects related to DEHP and DiNP exposure are necessary for the children.     

Breast cancer and persistent organic pollutants (excluding DDT): a systematic literature review

Persistent organic pollutants (POPs) are a group of heterogeneous compounds of both natural and anthropogenic origin with highly persistent and bioaccumulative properties. They cause a range of adverse effects to human health and the environment around the world. There is growing concern that POPs may increase breast cancer risk due to their xenoestrogenic properties. The aim of this systematic literature review is to summarize and integrate the risks of breast cancer following environmental exposure to POPs (other than DDT) from primary epidemiological studies published between 2006 and 2015. After searching various databases, 14 case-control studies and one cohort study were included. Evidence of an association between increased breast cancer risk and environmental exposure to these chemicals is inconsistent and inadequate to conclude with certainty. However, most of the studies have examined exposure to the pollutants after diagnosis of breast cancer, overlooking exposure during critical windows of vulnerability. They have also largely focused on individual chemicals but ignored the combined effects of different chemicals. Therefore, major data gaps remain in examining exposure during critical windows of vulnerability and assessing combined effects of multiple chemicals. Development of better exposure assessment methods addressing these gaps is required for future research.     

The use of wastewater in livestock production and its socioeconomic and welfare implications

Although epidemiological studies have found a significant amount of toxins in surface water, a complex link between animals’ access to wastewater and associated animal and human welfare losses needs to be explored. The scarcity of safe water has put stress on the utilization of wastewater for crops and livestock production. The access of animals to wastewater is related to the emergence of dangerous animal’s diseases, hampering productivity, increasing economic losses, and risking human health along the food chain. This review explores use of wastewater for agriculture, epidemiological evidence of microbial contamination in wastewater, and animal and human welfare disruption due to the use of wastewater for crop and livestock production. More specifically, the review delves into animals exposure to wastewater for bathing, drinking, or grazing on a pasture irrigated with contaminated water and related animal and human welfare losses. We included some scientific articles and reviews published from 1970 to 2017 to support our rational discussions. The selected articles dealt exclusively with animals direct access to wastewater via bathing and indirect access via grazing on pasture irrigated with contaminated wastewater and their implication for animal and human welfare losses. The study also identified that some policy options such as wastewater treatments, constructing wastewater stabilization ponds, controlling animal access to wastewater, and dissemination of necessary information to ultimate consumers related to the source of agricultural produce and wastewater use in animal and crop production are required to protect the human and animal health and welfare.     

Health Effects of Waste Incineration: A Review of Epidemiologic Studies

ABSTRACT

There is an increasing trend toward using incineration to solve the problem of waste management; thus, there are concerns about the potential health impact of waste incineration. A critical review of epidemiologic studies will enhance understanding of the potential health effects of waste incineration and will provide important information regarding what needs to be investigated further. This study reviews the epidemiologic research on the potential health impact of waste incineration. Previous studies are discussed and presented according to their study population, incinerator workers or community residents, and health end points. Several studies showed significant associations between waste incineration and lower male-to-female ratio, twinning, lung cancer, laryngeal cancer, ischemic heart disease, urinary mutagens and pro-mutagens, or blood levels of certain organic compounds and heavy metals. Other studies found no significant effects on respiratory symptoms, pulmonary function,twinning, cleft lip and palate, lung cancer, laryngeal cancer,or esophageal cancer. In conclusion, these epidemiologic studies consistently observed higher body levels of some organic chemicals and heavy metals, and no effects on respiratory symptoms or pulmonary function. The findings for cancer and reproductive outcomes were inconsistent. More hypothesis-testing epidemiologic studies are needed to investigate the potential health effects of waste incineration on incinerator workers and community residents.     

Health effects of waste incineration: a review of epidemiologic studies

There is an increasing trend toward using incineration to solve the problem of waste management; thus, there are concerns about the potential health impact of waste incineration. A critical review of epidemiologic studies will enhance understanding of the potential health effects of waste incineration and will provide important information regarding what needs to be investigated further. This study reviews the epidemiologic research on the potential health impact of waste incineration. Previous studies are discussed and presented according to their study population, incinerator workers or community residents, and health end points. Several studies showed significant associations between waste incineration and lower male-to-female ratio, twinning, lung cancer, laryngeal cancer, ischemic heart disease, urinary mutagens and promutagens, or blood levels of certain organic compounds and heavy metals. Other studies found no significant effects on respiratory symptoms, pulmonary function, twinning, cleft lip and palate, lung cancer, laryngeal cancer, or esophageal cancer. In conclusion, these epidemiologic studies consistently observed higher body levels of some organic chemicals and heavy metals, and no effects on respiratory symptoms or pulmonary function. The findings for cancer and reproductive outcomes were inconsistent. More hypothesis-testing epidemiologic studies are needed to investigate the potential health effects of waste incineration on incinerator workers and community residents.     

Occurrence and distribution of PCB metabolites in blood and their potential health effects in humans: a review

In recent years, attention has been directed to chemicals with possible endocrine-disrupting properties. Polychlorinated biphenyls (PCBs) and their metabolites belong to one group of environmental contaminants that have been shown to interact with the endocrine system in mammals, including humans. Although recent developments have been made in terms of determination of PCB metabolites in blood samples, still limited number of studies have been able to elucidate their profiles and toxicological and health effects in humans. This review aims to evaluate and compare the levels of hydroxylated PCBs (OH-PCBs) and methyl sulfone PCBs (MeSO₂-PCBs) in blood and their relationship to parent compounds and also address the potential risks and adverse health effects in humans. Levels of OH-PCBs varied between 0.0002 and 1.6 ng g^?1 w/w in human serum/plasma from the selected literature, correlating well with ∑PCBs. In contrast, ∑OH-PCB/∑PCB ratio in animals did not show a significant correlation, which might suggest that the bioaccumulation plays an even more important role in the concentration of OH-PCBs compared to PCB metabolism. Highest levels of MeSO₂-PCBs were reported in marine mammals with high selectivity retention in the liver. Health effects of PCB metabolites included carcinogenicity, reproductive impairment, and developmental neurotoxicity, being more efficiently transferred to the brain and across the placenta from mother to fetus in comparison to the parent PCBs. Based on the lack of knowledge on the occurrence and distribution of lower chlorinated OH-PCBs in humans, further studies to identify and assess the risks associated to human exposure are essential.     

Reproductive toxicity of lead,cadmium, and phthalate exposure in men

Environmental toxicants viz lead or cadmium and phthalate esters (di(2-ethylhexyl) phthalate [DEHP], dibutyl phthalate [DBP], and diethyl phthalate [DEP]) widely found in different environmental strata are linked to deteriorating male reproductive health. The objective was to assess the relationships between the seminal lead, cadmium, and phthalate (DEHP, DBP, DEP) concentrations at environmental level and serum hormone levels and semen quality in non-occupationally exposed men and specify the effect of individual and combined exposure of toxicants on semen quality. A study of 60 male partners of couples attending the Andrology Laboratory of the Reproductive Biology Department, All India Institute of Medical Sciences (AIIMS), New Delhi, India for semen analysis to assess their inability to achieve a pregnancy was selected for the study. The results of univariate and stepwise multiple regression analysis in the unadjusted model showed a significant correlation between lead or cadmium and phthalates DEHP/DBP/DEP and sperm motility, sperm concentration, and DNA damage. After adjusting for potential confounders, an association with lead or DEHP was only observed. The present data shows that lead (Pb) or cadmium (Cd) or phthalates might independently contribute to decline in semen quality and induce DNA damage. Phthalates might influence reproductive hormone testosterone. These findings are significant in light of the fact that men are exposed to a volley of chemicals; however, due to the small sample size, our finding needs to be confirmed in a larger population.     

Controlling the Flue-Fed Incinerator

This paper examines various health effects of photochemical air pollution in Japan, primarily through the review of epidemiological studies. Health effects discussed include subjective respiratory symptoms, respiratory function testing, ocular effects, and hospital diagnostic tests. The downward trend in oxidant cautions and paralleled health effects, as reported by the Japanese Environmental Agency, are discussed. The methods determined by Japanese ordinance for measurement of oxidants, SO₂, NO _x , and CO are described.     

Air Quality Criteria—Toxicological Appraisal for Oxidants,Nitrogen Oxides,and Hydrocarbons

The ultimate aim of toxicological studies is to determine the effects of pollutants on the health and welfare of human beings. To get this it is essential to conduct animal studies to evaluate the potential toxicity of different pollutants. Toxicological appraisal of the photochemical oxidant type of air pollution shows: (1) The effects are primarily on the lungs and the senses. (2) There is impairment of pulmonary function in humans at concentrations found in polluted air. (3) Both ozone and nitrogen dioxide tend to oxidize in animals the lung tissue for a time. This process creates agents which have the potential for cross-linking structural proteins, and this process initiates inflammation which accelerates cell turnover rates. Both crosslinking and cell turnover rates are factors in aging, which may thus be accelerated by years of repeated exposure to oxidants. (4) Long-term exposure to low levels of nitrogen dioxide can produce pre-emphasematous lesions in the lungs of rats and mice. Studies with other species are needed. (5) Ozone, nitrogen dioxide, and dilute irradiated car exhausts increase susceptibility to respiratory infection.

The constant search for more sophisticated and sensitive techniques to detect subtle changes indicative of pre-disease conditions should not be relaxed. Such techniques will provide chronic disease predictors of great relevance as air quality criteria.     

The impact of pesticides on oxidative stress level in human organism and their activity as an endocrine disruptor

Pesticides cause serious environmental and health problems both to humans and animals. The aim of this review is to discuss selected herbicides and fungicides regarding their mode of action and their influence on basic oxidative stress parameters and endocrine disruption properties tested in selected cell cultures in vitro. Because of numerous difficulties which animal studies are subject to, cell cultures are an excellent experimental model reflecting human exposure to different pesticides through all relevant routes. This experimental model can be used to monitor aggregate and cumulative pesticide exposures.     

The association between bisphenol A exposure and type-2 diabetes: a world systematic review

The present study was conducted to systematically review, analyze, and interpret all the relevant evidence in the literature on the possible link between exposure to bisphenol A (BPA) and the risk of type-2 diabetes mellitus (T2DM). We developed a comprehensive search strategy and used it to search Web of Science, Scopus, PubMed, and Google Scholar up to March 31, 2016, producing 3108 hits, of which 13 original papers were included. Findings of these studies were quite controversial; few studies indicated a significant positive association between BPA exposure and T2DM, while some other failed to detect such a relationship. Overall, it can be suggested that chance is unlikely the plausible explanation for the observed association between BPA exposure and T2DM. This was mainly because even in the negative studies some clues could be found in favor of a statistically significant relationship between BPA and T2DM. Additionally, some of the studies had shortcomings in defining the exposure and outcome measures, which, if present, might have led to underestimating the relationship between BPA exposure and T2DM. The theoretical plausibility of such a relationship found earlier in animal studies also supports this point. However, more definitive answer requires the conduct of future longitudinal studies, in which the possible association between BPA exposure and T2DM is assessed over much longer periods of time with more temporally robust BPA measurements. In addition, it would be quite beneficial if future studies be conducted in areas where data is still lacking (e.g., South America, Australia/Oceania, and Europe).

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Dioxins: WHO's tolerable daily intake (TDI) revisited

In December 1990, the World Health Organization (WHO) established a tolerable daily intake (TDI) of 10 pg/kg b.w. (body weight) for TCDD, based on liver toxicity, reproductive effects and immunotoxicity in experimental animals, and making use of kinetic data in humans and experimental animals. Since then new epidemiological and toxicological data have emerged, in particular with respect to neurodevelopmental and endocrine effects of dioxin. Therefore, the European Centre for Environment and Health of the World Health Organization (WHO-ECEH) and the International Programme on Chemical Safety (IPCS) jointly organized a consultation on the "Assessment of the health risk of dioxins: re-evaluation of the TDI", May 1998, Geneva, Switzerland. The participants discussed the health risks for infants, cancer and non-cancer endpoints in humans and animals, mechanistic aspects, kinetic behaviour, modelling, exposure, and the applicability of the toxic equivalency (TEQ) concept. For the health risk assessment of dioxin-like compounds, the WHO Consultation focused on the most sensitive effects that are considered adverse (hormonal, reproductive and developmental effects) seen at low doses in animal studies (rats and monkeys). Human daily intakes corresponding with body burdens similar to those associated with adverse effects in animals could be estimated to be in the range of 14-37 pg/kg b.w./day. To arrive at a TDI expressed as TEQ, a composite uncertainty factor of 10 was recommended. By applying this uncertainty factor a TDI range of 1-4 pg TEQs/kg body weight was established. An extensive executive summary of the results of this WHO Consultation with all the underlying background documents will be published in Food Additives and Contaminants (in press).     

Association of individual green space exposure with the incidence of asthma and allergic rhinitis: a systematic review and meta-analysis

The association between allergic respiratory diseases, such as asthma and allergic rhinitis (AR), and green space (GS) remains controversial. Our study aimed to summarize and synthesize the association between individual GS exposure and the incidence of asthma/AR. We systematically summarized the qualitative relationship between GS exposure and asthma and AR. The pooled odds ratio (OR) with 95% confidence intervals (CIs) was used to estimate the effect of the Normalized Difference Vegetation Index (NDVI) on asthma and AR. A total of 21 studies were included for systematic review, and 8 of them underwent meta-analysis. In the meta-analysis of current asthma, the 0?<?radius?≤?100 m group, 100?<?radius?≤?300 m group, and 500?<?radius?≤?1000 m group presented weak negative associations between the NDVI and current asthma. For ever asthma, slight positive associations existed in the 0?<?radius?≤?100 m group and 300?<?radius?≤?500 m group. In addition, the NDVI might slightly reduce the risk of AR in radius of 100 m and 500 m. Our findings suggest that the effects of GS exposure on asthma and AR were not significant. Differences in GS measurements, disease diagnoses and adjusted confounders across studies may have an impact on the results. Subsequent studies should consider potential confounding factors and use more accurate GS exposure measurements to better understand the impact of GS exposure on respiratory disease in the population.

     

Methylmercury, fish consumption, and the precautionary principle

This paper considers several broad issues in the context of probabilistic assessment of the benefits of curtailing mercury (Hg) emissions from U.S. coal-fired power plants, based on information developed from recent literature and epidemiology studies of health effects of methylmercury. Exposure of the U.S. population is considered on the national scale, in large part because of recent questions arising from survey and experimental data about the relative importance of local deposition of airborne Hg. Although epidemiological studies have provided useful information, safe levels of Hg exposure remain uncertain, in part because of other dietary considerations in the populations that were studied. For example, much of the seafood consumed in one of the major studies was also contaminated with polychlorinated biphenyls, as are fish taken from some U.S. fresh waters. The primary epidemiological approach involves cross-study comparisons in relation to mean exposures, rather than detailed critiques of individual effects reported in each study. U.S. exposures are seen to be well below the levels at which adverse health effects are reported. This analysis supports the conclusion that unilateral reduction of Hg emissions from U.S. coal-fired power plants alone is unlikely to realize significant public health benefits.     

Increased urinary 8-hydroxy-2��-deoxyguanosine levels in workers exposed to di-(2-ethylhexyl) phthalate in a waste plastic recycling site in China

Background

Di-(2-ethylhexyl) phthalate (DEHP) is a common plasticizer used in industrial and diverse consumer products. Animal studies indicate DEHP caused developmental, reproductive, and hepatic toxicities. However, human studies of the potential effects of DEHP are limited.

Methods

The exposed site with a history of over 20 years of waste plastic recycling was located in Hunan Province, China. The reference site without known DEHP pollution source was about 50 km far away from the exposed site. In this study, 181 workers working in plastic waste recycling and 160 gender?Cage matched farmers were recruited. DEHP concentrations in water and cultivated soil samples, serum thyroid-stimulating hormone, malondialdehyde (MDA), superoxide dismutase (SOD), urinary 8-hydroxy-2??-deoxyguanosine (8-OHdG), and micronuclei frequency in human capillary blood lymphocytes were analyzed.

Results

Mean levels of DEHP were greater in environment at the recycling site than at reference site (industry wastewater for the exposed: 42.43 ??g/l; well water: 14.20 vs. 0.79 ??g/l, pond water: 135.68 vs. 0.37 ??g/l, cultivated soil: 13.07 vs. 0.81 mg/kg, p?p?p?Conclusions The occupational DEHP exposure might contribute to oxidative deoxyribonucleic acid damage in the male workers.     

Effects of airborne volatile organic compounds on plants

Routine measurements of volatile organic compounds (VOCs) in air have shown that average concentrations are very much smaller than those used in laboratory experiments designed to study the effects of VOCs on plants. However, maximum hourly concentrations of some VOCs can be 100 times larger than the average, even in rural air. Experimental studies have rarely extended for longer than a few days, so there is little information on potential long-term effects of exposure to small concentrations. This review considers the available evidence for long-term effects, based on laboratory and field data. Previous reviews of the literature from Germany and the USA are cited, prior to an assessment of the effects of individual VOCs. Although hydrocarbons from vehicle exhausts have been implicated in the observed effects on roadside vegetation, the evidence suggests that it is the nitrogen oxides in the exhaust gases that are mostly responsible. There is evidence that aromatic hydrocarbons can be metabolised in plants, although the fate of the metabolites is not known. There is a large literature on the effects of ethylene, because of its role as a plant hormone. Effects have been reported in the field, in response to industrial emissions, and dose-response experiments over several weeks in laboratory studies have clearly identified the potential for effects at ambient concentrations. The main responses are morphological (e.g. epinasty), which may be reversible, and on the development of flowers and fruit. Effects on seed production may be positive or negative, depending on the exposure concentration. Chlorinated hydrocarbons have been identified as potentially harmful to vegetation, but only one long-term experiment has studied dose-response relationships. As for ethylene, the most sensitive indication of effect was on seed production, although long-term accumulation of trichloroacetic acid in tissue may also be a problem. There is little evidence of the direct effects of oxygenated hydrocarbons on plants. Plants are a significant emission source of short-chain alcohols, aldehydes and ketones. Peroxyacetyl nitrate (PAN) has a well-documented history as damaging to vegetation. There have been few long-term experimental studies despite the field evidence for damaging effects. Early studies in California have been followed by more recent data from east Asia, but there is still a dearth of information on the potential for effects of PAN and related peroxyacyl nitrates on vegetation typical of regions around tropical and sub-tropical cities where PAN pollution is increasingly important. The lack of long-term measurements, coupled with the available evidence that effects are not linearly related to 'dose' measured as the product of exposure concentration and time, means that the possibility of adverse effects of VOCs on vegetation cannot be safely rejected, particularly in urban and industrial areas. Although reproductive processes (flowering, seed production) appear to be most sensitive, there have been no experimental studies on subsequent seed viability and the consequences at the ecosystem level of changes to plant phenology. The potential for VOC metabolites to accumulate in plant tissue has been demonstrated, but any subsequent effects on herbivores and phytophagous insects have yet to be investigated.