Prenatal phthalate exposures and anogenital distance in Swedish boys.

BACKGROUND: Phthalates are used as plasticizers in soft polyvinyl chloride (PVC) and in a large number of consumer products. Because of reported health risks, diisononyl phthalate (DiNP) has been introduced as a replacement for di(2-ethylhexyl) phthalate (DEHP) in soft PVC. This raises concerns because animal data suggest that DiNP may have antiandrogenic properties similar to those of DEHP. The anogenital distance (AGD)--the distance from the anus to the genitals--has been used to assess reproductive toxicity. OBJECTIVE: The objective of this study was to examine the associations between prenatal phthalate exposure and AGD in Swedish infants. METHODS: AGD was measured in 196 boys at 21 months of age, and first-trimester urine was analyzed for 10 phthalate metabolites of DEP (diethyl phthalate), DBP (dibutyl phthalate), DEHP, BBzP (benzylbutyl phthalate), as well as DiNP and creatinine. Data on covariates were collected by questionnaires. RESULTS: The most significant associations were found between the shorter of two AGD measures (anoscrotal distance; AGDas) and DiNP metabolites and strongest for oh-MMeOP [mono-(4-methyl-7-hydroxyloctyl) phthalate] and oxo-MMeOP [mono-(2-ethyl-5-oxohexyl) phthalate]. However, the AGDas reduction was small (4%) in relation to more than an interquartile range increase in DiNP exposure. CONCLUSIONS: These findings call into question the safety of substituting DiNP for DEHP in soft PVC, particularly because a shorter male AGD has been shown to relate to male genital birth defects in children and impaired reproductive function in adult males and the fact that human levels of DiNP are increasing globally.

The SELMA study: a birth cohort study in Sweden following more than 2000 mother-child pairs.

BACKGROUND: This paper describes the background, aim and study design for the Swedish SELMA study that aimed to investigate the importance of early life exposure during pregnancy and infancy to environmental factors with a major focus on endocrine disrupting chemicals for multiple chronic diseases/disorders in offspring. METHODS: The cohort was established by recruiting women in the 10th week of pregnancy. Blood and urine from the pregnant women and the child and air and dust from home environment from pregnancy and infancy period have been collected. Questionnaires were used to collect information on life styles, socio-economic status, living conditions, diet and medical history. RESULTS: Of the 8394 reported pregnant women, 6658 were invited to participate in the study. Among the invited women, 2582 (39%) agreed to participate. Of the 4076 (61%) non-participants, 2091 women were invited to a non-respondent questionnaire in order to examine possible selection bias. We found a self-selection bias in the established cohort when compared with the non-participant group, e.g. participating families did smoke less (14% vs. 19%), had more frequent asthma and allergy symptoms in the family (58% vs. 38%), as well as higher education among the mothers (51% vs. 36%) and more often lived in single-family houses (67% vs. 60%). CONCLUSIONS: These findings indicate that the participating families do not fully represent the study population and thus, the exposure in this population. However, there is no obvious reason that this selection bias will have an impact on identification of environmental risk factors.

Multicentre patch test study of air-oxidized ethoxylated surfactants.

Frequent exposure to water and surfactants is considered to be the main cause of hand eczema from wet work. Ethoxylated surfactants are susceptible to oxidation and some of the oxidation products formed have proved to be contact sensitizers in guinea pigs. The question of human sensitization to oxidized surfactants was addressed in a multicentre study in the Stockholm region. 528 consecutive dermatitis patients were patch tested with widely used ethoxylated surfactants in oxidized and non-oxidized form as well as certain identified oxidation compounds. 61 patients presented with mild, clearly irritant reactions to some of the surfactants tested. 18 patients showed not only erythema but also oedema and/or papules and vesicles, using a morphologic descriptive system for reading the patch test reactions. These reactions occurred mostly to oxidized surfactants and oxidation products. When retesting 9 of these 18 patients only an allergic reaction to acetaldehyde was confirmed. We conclude that oxidized ethoxylated surfactants have increased irritant potential compared to non-oxidized material. Our working hypothesis is that oxidized surfactants of technical quality exert a lower risk of sensitization than do oxidized homologous pure surfactants. Among the potential allergens formed during autoxidation, formaldehyde and acetaldehyde must be considered as a source of unexpected exposure.

Structure elucidation, synthesis, and contact allergenic activity of a major hydroperoxide formed at autoxidation of the ethoxylated surfactant C12E5.

Ethoxylated alcohols, widely used as surfactants, are known to be susceptible to oxidation when exposed to air. At autoxidation, a complex mixture is formed, in which alkyl poly(ethylene glycol) aldehydes, alkyl poly(ethylene glycol) formates, hydroxyaldehydes, and formaldehyde have previously been identified. These compounds are all secondary oxidation products, some of which have been shown to be skin sensitizers and irritants. The primary oxidation products from ethoxylated alcohols are described in the literature as peroxides and hydroperoxides, but their structures have not been elucidated more closely. Peroxides and hydroperoxides are usually reactive species and can be suspected to be biologically active as skin sensitizers and irritants. In the present investigation, we studied the autoxidation of the pure ethoxylated alcohol pentaethylene glycol mono-n-dodecyl ether (C(12)E(5)), using NMR and HPLC-MS. On the basis of experience from previous studies on a small model compound, diethyleneglycol monoethyl ether (C(2)E(2)), the hydroperoxide expected to be found in the highest amount in autoxidized C(12)E(5) was synthesized and used as a reference substance in the analyses. This same hydroperoxide, 16-hydroperoxy-3,6,9,12,15-pentaoxaheptacosan-1-ol, was identified in the autoxidation mixture of C(12)E(5), and its sensitizing capacity was determined. It was found to be a moderate allergen in experimental sensitization studies in guinea pigs. Our data further indicate the presence of at least three additional hydroperoxides in the autoxidation mixture of C(12)E(5), one of which was identified as 1-hydroperoxy-3,6,9,12,15-pentaoxaheptacosan-1-ol. The results accentuate the importance of controlling the storage, transportation, and handling conditions of ethoxylated surfactants, to avoid the formation of allergenic and skin irritant oxidation products.

Primary oxidation products affect the quantification of formaldehyde in autoxidized fatty alcohol ethoxylates when using DNPH derivatization.

Non-ionic surfactants, e.g. fatty alcohol ethoxylates, are considered to cause less skin irritation than other types of surfactants. However, the autoxidation of alcohol ethoxylates generates products that are both skin irritating and sensitizing, such as formaldehyde. It has been suggested that formaldehyde be used as an indicator of the degree of autoxidation of fatty alcohol ethoxylates, and thus also as an indicator of the sensitizing capacity of the product. Attempts to analyse formaldehyde in autoxidized ethoxylates using 2,4-dinitrophenylhydrazine derivatization resulted in formation of the corresponding hydrazone not only from free formaldehyde but also from autoxidation products during the derivatization reaction. Consequently, this derivatizing agent is inappropriate for the determination of formaldehyde in autoxidized fatty alcohol ethoxylates. Focus on the content of primary oxidation products, i.e. hydroperoxides/peroxides, is suggested, particularly as they also are potent sensitizers.

Allergenic activity of an air-oxidized ethoxylated surfactant.

Ethoxylated surfactants are used in household and industrial cleaners, topical pharmaceuticals, cosmetics and laundry products. Polyethers, e.g. ethoxylated surfactants and polyethylene glycols, are oxidized by atmospheric oxygen (autoxidized) when stored and handled. We have previously shown that a chemically well-defined non-ionic surfactant, the ethoxylated alcohol penta-ethylene glycol mono-n-dodecyl ether (C12E5), forms a complex mixture of autoxidation products when exposed to air. Predictive testing in guinea pigs showed that the surfactant itself is a non-sensitizer, but that oxidation products formed are skin sensitizers. The aim of this study was to investigate the sensitizing capacity of a total oxidation mixture of C12E5 obtained after autoxidation. The allergenic activity of different oxidation products is discussed as well as the clinical importance of the findings. This study shows that the non-ionic surfactant C12E5 containing 20% oxidation products is a sensitizing mixture. The result accords with what is observed for other compounds that are unstable when in contact with air, e.g. limonene and linalool, major fragrance terpenes. Studies regarding the clinical relevance of our findings should be performed. However, it is already clear from this study that precautions must be taken in handling and storage of ethoxylated surfactants to avoid formation of allergenic mixtures.