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Numerous contaminants in indoor air and their potential to cause or exacerbate asthma continue to be a subject of public health concern. Many agents are causally associated with or can exacerbate asthma, particularly in children. For formaldehyde, an established respiratory irritant based on numerous studies, the evidence for an association with asthma is still considered only limited or suggestive. However, there is no evidence that indicates increased sensitivity to sensory irritation to formaldehyde in people often regarded as susceptible such as asthmatics. Acrolein, but not formaldehyde, was significantly associated with asthma in a large cohort of children. This prompted an evaluation of this highly irritating chemical that had never previously been considered in the context of the indoor air/childhood asthma issue. Because acrolein is more potent than formaldehyde as a respiratory irritant and ubiquitous in indoor air, it is plausible that previous studies on potential risk factors and childhood asthma may be confounded by formaldehyde acting as an unrecognized proxy for acrolein., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Formaldehyde is a well-studied chemical and effects from inhalation exposures have been extensively characterized in numerous controlled studies with human volunteers, including asthmatics and other sensitive individuals, which provide a rich database on exposure concentrations that can reliably produce the symptoms of sensory irritation. Although individuals can differ in their sensitivity to odor and eye irritation, the majority of authoritative reviews of the formaldehyde literature have concluded that an air concentration of 0.3 ppm will provide protection from eye irritation for virtually everyone. A weight of evidence-based formaldehyde exposure limit of 0.1 ppm (100 ppb) is recommended as an indoor air level for all individuals for odor detection and sensory irritation. It has recently been suggested by the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and the US Environmental Protection Agency (US EPA) that formaldehyde is causally associated with nasopharyngeal cancer (NPC) and leukemia. This has led US EPA to conclude that irritation is not the most sensitive toxic endpoint and that carcinogenicity should dictate how to establish exposure limits for formaldehyde. In this review, a number of lines of reasoning and substantial scientific evidence are described and discussed, which leads to a conclusion that neither point of contact nor systemic effects of any type, including NPC or leukemia, are causally associated with exposure to formaldehyde. This conclusion supports the view that the equivocal epidemiology studies that suggest otherwise are almost certainly flawed by identified or yet to be unidentified confounding variables. Thus, this assessment concludes that a formaldehyde indoor air limit of 0.1 ppm should protect even particularly susceptible individuals from both irritation effects and any potential cancer hazard.

Drawing on all data available in 2003, the WoE of the human epidemiological data for polychlorinated biphenyls (PCBs) demonstrates that exposure to a mixture of PCBs (i.e. Aroclors) did not pose a cancer risk to humans ( Golden et al. (2003) . This evaluation was based on criteria established by the US Environmental Protection Agency (EPA) as well as on a different methodology used by the Agency for Toxic Substances and Disease Registry (ATSDR). Subsequently, at least 15 more studies on the potential cancer risks (both incidence and mortality) of PCBs have been published. All studies published since 2003 are critically reviewed using the criteria established by the EPA (2005) and ATSDR (2000) . None of the studies published since 2003 change the conclusions drawn by Golden et al. (2003) : "that the weight of evidence does not support a causal association for PCBs and human cancer". This conclusion pertains to all cancers combined, as well as to the various cancers that have been sporadically reported in the occupational cohort mortality studies. With respect to breast cancer risk, the WoE is compelling that environmental exposure to PCBs is not etiologically implicated in breast-cancer risk. This conclusion is supported by the consistently negative findings for increased breast-cancer mortality in occupational studies, which now involve almost 9,000 women occupationally exposed to PCBs. Similarly, the incidence studies in which PCB background levels are reported to be associated with increased risk of non-Hodgkin's lymphoma or prostate, testicular, and intestinal cancer are not corroborated by occupational cohort studies with PCB exposures far in excess of environmental exposures. The most likely explanation for these discordant findings is discussed in this review. Finally, the recent elucidation of the mode of action by which PCBs promote liver tumors in rats, combined with the demonstration that none of the key events in the mode of action occurred until substantial tissue accumulation of total PCBs had occurred, casts further doubt that PCB exposure at environmental or occupational levels poses a carcinogenic risk to humans. The dramatic differences between rodents and humans in sensitivity to PCB-mediated induction of CYP1A1 suggests that even occupational exposures to PCBs have never resulted in PCB body burdens approaching the levels required to initiate the sequence of events involved in the promotion of liver tumors in rodents.

The United States Environmental Protection Agency (EPA) recently proposed a hypothetical mode of action (MOA) to explain how inhaled formaldehyde (FA) might induce leukemia, lymphoma and a variety of other lymphohematopoietic (LHP) malignancies in occupationally exposed workers. The central hypothesis requires that B lymphocytes or hematopoietic progenitor cells (HPC) present at the "portal of entry (POE)" undergo sustained mutagenic change as a result of direct FA exposure. These modified cells would then migrate back to the bone marrow or primary lymphatic tissue and subsequently develop into specific LHP disease states. Chemical interaction at the POE is an absolute requirement for the hypothesized MOA as there is no convincing evidence that inhaled FA causes distant site (e.g., bone marrow) toxicity. The purpose of this review is to critically evaluate this proposed MOA within the context of the existing data concerning the toxicokinetic and biological properties of FA, the current understanding of the induction of chemically-induced leukemias and lymphomas, as well as within EPA's specific guidelines for evaluating the MOA of chemically-induced cancers. Specifically, we examine the scientific support for the hypothesis that FA exposure may induce carcinogenic transformation of localized lymphocytes or peripheral hematopoietic progenitor cells (HPC) in the absence of discernable systemic hematopoietic toxicity (i.e., peripheral transformation). While little or no empirical evidence exists upon which to fully evaluate the proposed hypothesis, available data does not support the proposed concept of "peripheral transformation" at the chemical entry site. Numerous animal bioassays evaluating chronic inhalation of FA clearly do not support this hypothesis since no properly conducted study as ever shown an increase in any LHP malignancy. Moreover, the notion that FA can cause any LHP malignancy is not supported with either epidemiologic data or current understanding of differing etiologies and risk factors for the various hematopoietic and lymphoproliferative malignancies. It is therefore concluded that existing science does not support the proposed MOA as a logical explanation for proposing that FA is a realistic etiological factor for any LHP malignancy.

The International Agency for Research on Cancer (IARC, 2004) recently reevaluated the epidemiological data on formaldehyde and concluded that there was "strong but not sufficient evidence for a causal association between leukaemia and occupational exposure to formaldehyde." This conclusion was tempered since a mechanism for leukemia induction could not be identified. Chemically induced leukemia is a well-studied phenomenon with benzene and a number of cancer chemotherapeutic drugs recognized as capable of causing this effect. Abundant in vitro and in vivo data in animals and humans demonstrate that exposure to sufficient doses of these recognized leukemogens can initiate a cascade of events leading to hematopoietic toxicity and the subsequent development of leukemia. This review addresses the biological plausibility that formaldehyde might be capable of causing any type of leukemia by providing a broad overview of the scientific data that must be considered in order to support or refute a conclusion that a particular substance might be leukemogenic. Data on benzene and selected chemotherapeutic cancer drugs are used as examples and are briefly summarized to demonstrate the similar biological events thought to result in leukemogenesis. These data are compared and contrasted with the available data on formaldehyde in order to judge whether they fulfill the criteria of biological plausibility that formaldehyde would be capable of inducing leukemia as suggested by the epidemiological data. Based on the epidemiological data, it is reasonable to expect that if formaldehyde was capable of inducing leukemia, in vivo and in vitro data would offer supporting evidence for biological plausibility. In particular, there is (1) no evidence to suggest that formaldehyde reaches any target organ beyond the site of administration including the bone marrow, (2) no indication that formaldehyde is toxic to the bone marrow/hematopoietic system in in vivo or in vitro studies, and (3) no credible evidence that formaldehyde induces leukemia in experimental animals. As discussed in this review, based on the key biological events that occur in the process of chemically induced leukemia, there is inadequate biological evidence currently available to corroborate existing weak epidemiological associations. This provides an insufficient database to conclude that there is a causal relationship for formaldehyde and leukemia risk.

Parabens are a group of the alkyl esters of p-hydroxybenzoic acid and typically include methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, isopropylparaben, and benzylparaben. Parabens (or their salts) are widely used as preservatives in cosmetics, toiletries, and pharmaceuticals due to their relatively low toxicity profile and a long history of safe use. Testing of parabens has revealed to varying degrees that individual paraben compounds have weakly estrogenic activity in some in vitro screening tests, such as ligand binding to the estrogen receptor, regulation of CAT gene expression, and proliferation of MCF-7 cells. Reported in vivo effects include increased uterine weight (i.e., butyl-, isobutyl-, and benzylparaben) and male reproductive-tract effects (i.e., butyl- and propylparaben). However, in relation to estrogen as a control during in vivo studies, the parabens with activity are many orders of magnitude less active than estrogen. While exposure to sufficient doses of exogenous estrogen can increase the risk of certain adverse effects, the presumption that similar risks might also result from exposure to endocrine-active chemicals (EACs) with far weaker activity is still speculative. In assessing the likelihood that exposure to weakly active EACs might be etiologically associated with adverse effects due to an endocrine-mediated mode of action, it is paramount to consider both the doses and the potency of such compounds in comparison with estrogen. In this review, a comparative approach involving both dose and potency is used to assess whether in utero or adult exposure to parabens might be associated with adverse effects mediated via an estrogen-modulating mode of action. In utilizing this approach, the paraben doses required to produce estrogenic effects in vivo are compared with the doses of either 17beta-estradiol or diethylstilbestrol (DES) that are well established in their ability to affect endocrine activity. Where possible and appropriate, emphasis is placed on direct comparisons with human data with either 17beta-estradiol or DES, since this does not require extrapolation from animal data with the uncertainties inherent in such comparisons. Based on these comparisons using worst-case assumptions pertaining to total daily exposures to parabens and dose/potency comparisons with both human and animal no-observed-effect levels (NOELs) and lowest-observed-effect levels (LOELs) for estrogen or DES, it is biologically implausible that parabens could increase the risk of any estrogen-mediated endpoint, including effects on the male reproductive tract or breast cancer. Additional analysis based on the concept of a hygiene-based margin of safety (HBMOS), a comparative approach for assessing the estrogen activities of weakly active EACs, demonstrates that worst-case daily exposure to parabens would present substantially less risk relative to exposure to naturally occurring EACs in the diet such as the phytoestrogen daidzein.

Unlabelled: According to the United Nations, global fertility has declined in the last century as reflected by a decline in birth rates. The earth's surface air temperature has increased considerably and is referred to as global warming. Since changes in temperature are well known to influence fertility we sought to determine if a statistical relationship exists between long-term changes in global air temperatures and birth rates. The most complete and reliable birth rate data in the 20th century was available in 19 industrialized countries. Using bivariate and multiple regression analysis, we compared yearly birth rates from these countries to global air temperatures from 1900 to 1994.A common pattern of change in birth rates was noted for the 19 industrialized countries studied. In general, birth rates declined markedly throughout the century except during the baby boom period of approximately 1940 to 1964. An inverse relationship was found between changes in global temperatures and birth rates in all 19 countries. Controlling for the linear yearly decline in birth rates over time, this relationship remained statistically significant for all the 19 countries in aggregate and in seven countries individually (p<0.05)., Conclusions: The results of our analyses are consistent with the underlying premise that temperature change affects fertility and suggests that human fertility may have been influenced by change in environmental temperatures.

Purpose: Children born to older parents are at greater risk for genetic abnormalities, such as Down syndrome. The influence of maternal age on Down syndrome is well established but little is known about the genetic consequences of advanced paternal age., Materials and Methods: Data on the incidence of Down syndrome from 1983 to 1997 (3,419 cases) were obtained from the New York State Department of Health congenital malformations registry. Parental age was modeled as individual age groups and by a single linear covariate (drift model). The log linear chi-square test and a test of significance of different explanatory variables were used to evaluate these models to determine significance. We compared actual Down syndrome rates by maternal age with the estimated rate corrected for paternal age., Results: From 1983 to 1997 a dramatic increase in the number of infants born to parents 35 years or older was observed. During the 15-year study period there was an increase of 111% and 60% in the number of mothers and fathers 35 years old or older, respectively. There was no parental age influence on Down syndrome until age 35 years and older. A paternal age effect was seen in association with a maternal age of 35 years and older, and it was most pronounced when maternal age was 40 years and older (p = 0.0004). In this later maternal age group the paternal contribution to Down syndrome was 50%., Conclusions: Advanced paternal age combined with maternal age significantly influences the incidence of Down syndrome. This effect may represent a paradigm for other genetic abnormalities in children of older fathers.

In 1999 the Agency for Toxic Substances and Disease Registry (ATSDR) released a Draft Toxicological Profile for Polychlorinated Biphenyls (PCBs). In reviewing the potential human carcinogenicity of PCBs, ATSDR (1999) concluded that "The weight of evidence does not support a causal association for PCBs and human cancer at this time." Just 1 year later, in an updated Toxicological Profile for Polychlorinated Biphenyls (PCBs), the conclusions of another analysis (ATSDR, 2000) on whether exposure to PCBs might represent a carcinogenic risk to humans had dramatically changed to "Overall, the human studies provide some evidence that PCBs are carcinogenic" and "some of these studies provide meaningful evidence that PCBs are carcinogenic in humans." Because this is a substantially different conclusion than that reached only one year previously, it raises a number of questions that must be considered particularly since "weight of evidence" has a precise meaning in the context of evaluating a body of epidemiological data. The present review addresses the additional scientific data that became available between the ATSDR 1999 and 2000 evaluations that was of a magnitude to offset the weight of evidence from numerous epidemiological studies that exposure to PCBs was not causally associated with human cancer to a conclusion only 1 year later that there was now "meaningful evidence" that PCBs posed a carcinogenic risk to humans. Also of interest are the criteria upon which this conclusion is based and the distinction between "weight of evidence" and the newer descriptors of "some evidence" and "meaningful evidence." However, as shown in this review, only one relevant study was published between the ATSDR 1999 and 2000 evaluations and the results of this study were unequivocally supportive of the 1999 conclusion. Because of the continuing controversy surrounding this issue, in this review, all relevant epidemiological data on PCBs are summarized and subjected to another weight of evidence evaluation. This critical review is based on the most recent guidelines (U.S. EPA, 1999a, 2003) for conducting weight-of-evidence evaluations on a body of epidemiological data. Applying a weight-of-evidence evaluation to the PCB epidemiological studies can only lead to the conclusion that there is no causal relationship between PCB exposure and any form of cancer, thereby confirming the conclusions of ATSDR (1999). Also considered is the methodology and logic used by ATSDR (2000) that resulted in overturning the weight of evidence conclusions concerning the human carcinogenicity of PCBs in ATSDR (1999). This issue may have public health and policy implications. It seems appropriate that unbiased evaluations of a body of data, even of controversial issues such as the potential human carcinogenicity of PCBs, be conducted in a transparent manner following applicable guidelines. The dramatic differences between the conclusions of ATSDR (1999) and ATSDR (2000) do not appear to be consistent with this process.