Mattias Öberg

Worldwide burden of disease from exposure to second-hand smoke: a retrospective analysis of data from 192 countries

BACKGROUND Exposure to second-hand smoke is common in many countries but the magnitude of the problem worldwide is poorly described. We aimed to estimate the worldwide exposure to second-hand smoke and its burden of disease in children and adult non-smokers in 2004. METHODS The burden of disease from second-hand smoke was estimated as deaths and disability-adjusted life-years (DALYs) for children and adult non-smokers. The calculations were based on disease-specific relative risk estimates and area-specific estimates of the proportion of people exposed to second-hand smoke, by comparative risk assessment methods, with data from 192 countries during 2004. FINDINGS Worldwide, 40% of children, 33% of male non-smokers, and 35% of female non-smokers were exposed to second-hand smoke in 2004. This exposure was estimated to have caused 379,000 deaths from ischaemic heart disease, 165,000 from lower respiratory infections, 36,900 from asthma, and 21,400 from lung cancer. 603,000 deaths were attributable to second-hand smoke in 2004, which was about 1·0% of worldwide mortality. 47% of deaths from second-hand smoke occurred in women, 28% in children, and 26% in men. DALYs lost because of exposure to second-hand smoke amounted to 10·9 million, which was about 0·7% of total worldwide burden of diseases in DALYs in 2004. 61% of DALYs were in children. The largest disease burdens were from lower respiratory infections in children younger than 5 years (5,939,000), ischaemic heart disease in adults (2,836,000), and asthma in adults (1,246,000) and children (651,000). INTERPRETATION These estimates of worldwide burden of disease attributable to second-hand smoke suggest that substantial health gains could be made by extending effective public health and clinical interventions to reduce passive smoking worldwide. FUNDING Swedish National Board of Health and Welfare and Bloomberg Philanthropies.

Exposure to dioxin-like pollutants via different food commodities in Swedish children and young adults

The dietary intake of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) in terms of toxic equivalents (TEQs) was investigated in Swedish children and young adults. Exposure was estimated from concentration data of six groups of individual food commodities (meat, fish, dairy products, egg, edible fats and other foodstuff) combined with food intake data from a 7-day record book obtained from 670 individuals aged 1-24 years. The results showed that Swedish boys and girls, up to the age of ten, had a median TEQ intake that exceeded the tolerable daily intake (TDI) of 2 pg TEQ/kg body weight. Children exceeding the TDI varied from almost all individuals among the youngest children to about 20% among young men and women. Dairy and fish products were the main sources of exposure for the average child, accounting for 59% of the total TEQ intake. The individuals most highly exposed were, on the other hand, characterized by a high consumption of fish. Since children constitute a vulnerable group, results obtained from the present study show that it is essential to perform age specific dietary intake assessments of pollutants and more carefully consider sensitive and/or highly exposed groups in the population in the risk management processes.

Strategic focus on 3R principles reveals major reductions in the use of animals in pharmaceutical toxicity testing.

The principles of the 3Rs, Replacement, Reduction and Refinement, are being increasingly incorporated into legislations, guidelines and practice of animal experiments in order to safeguard animal welfare. In the present study we have studied the systematic application of 3R principles to toxicological research in the pharmaceutical industry, with particular focus on achieving reductions in animal numbers used in regulatory and investigatory in vivo studies. The work also details major factors influencing these reductions including the conception of ideas, cross-departmental working and acceptance into the work process. Data from 36 reduction projects were collected retrospectively from work between 2006 and 2010. Substantial reduction in animal use was achieved by different strategies, including improved study design, method development and project coordination. Major animal savings were shown in both regulatory and investigative safety studies. If a similar (i.e. 53%) reduction had been achieved simultaneously within the twelve largest pharmaceutical companies, the equivalent reduction world-wide would be about 150,000 rats annually. The results point at the importance of a strong 3R culture, with scientific engagement, collaboration and a responsive management being vital components. A strong commitment in leadership for the 3R is recommended to be translated into cross-department and inter-profession involvement in projects for innovation, validation and implementation. Synergies between all the three Rs are observed and conclude that in silico-, in vitro- and in vivo-methods all hold the potential for applying the reduction R and should be consequently coordinated at a strategic level.

Uppsala Consensus Statement on Environmental Contaminants and the Global Obesity Epidemic

Summary: From the lectures presented at the 2nd International Workshop on Obesity and Environmental Contaminants, which was held in Uppsala, Sweden, on 8–9 October 2015, it became evident that the findings from numerous animal and epidemiological studies are consistent with the hypothesis that environmental contaminants could contribute to the global obesity epidemic. To increase awareness of this important issue among scientists, regulatory agencies, politicians, chemical industry management, and the general public, the authors summarize compelling scientific evidence that supports the hypothesis and discuss actions that could restrict the possible harmful effects of environmental contaminants on obesity.

Aerial application of mancozeb and urinary ethylene thiourea (ETU) concentrations among pregnant women in Costa Rica: the Infants' Environmental Health Study (ISA).

Background: Mancozeb and its main metabolite ethylene thiourea (ETU) may alter thyroid function; thyroid hormones are essential for fetal brain development. In Costa Rica, mancozeb is aerially sprayed at large-scale banana plantations on a weekly basis. Objectives: Our goals were to evaluate urinary ETU concentrations in pregnant women living near large-scale banana plantations, compare their estimated daily intake (EDI) with established reference doses (RfDs), and identify factors that predict their urinary ETU concentrations. Methods: We enrolled 451 pregnant women from Matina County, Costa Rica, which has large-scale banana production. We visited 445 women up to three times during pregnancy to obtain urine samples (n = 872) and information on factors that possibly influence exposure. We determined urinary ETU concentrations using liquid chromatography mass spectrometry. Results: Pregnant women’s median urinary ETU concentrations were more than five times higher than those reported for other general populations. Seventy-two percent of the women had EDIs above the RfD. Women who lived closest (1st quartile, < 48 m) to banana plantations on average had a 45% (95% CI: 23, 72%) higher urinary ETU compared with women who lived farthest away (4th quartile, ≥ 565 m). Compared with the other women, ETU was also higher in women who washed agricultural work clothes on the day before sampling (11%; 95% CI: 4.9, 17%), women who worked in agriculture during pregnancy (19%; 95% CI: 9.3, 29%), and immigrant women (6.2%; 95% CI: 1.0, 13%). Conclusions: The pregnant women’s urinary ETU concentrations are of concern, and the principal source of exposure is likely to be aerial spraying of mancozeb. The factors predicting ETU provide insight into possibilities for exposure reduction. Citation: van Wendel de Joode B, Mora AM, Córdoba L, Cano JC, Quesada R, Faniband M, Wesseling C, Ruepert C, Öberg M, Eskenazi B, Mergler D, Lindh CH. 2014. Aerial application of mancozeb and urinary ethylene thiourea (ETU) concentrations among pregnant women in Costa Rica: The Infants’ Environmental Health Study (ISA). Environ Health Perspect 122:1321–1328; http://dx.doi.org/10.1289/ehp.1307679

Indigenous children living nearby plantations with chlorpyrifos-treated bags have elevated 3,5,6-trichloro-2-pyridinol (TCPy) urinary concentrations

BACKGROUND The US Environmental Protection Agency voluntary phased-out residential use of chlorpyrifos in 2001. In contrast, in Costa Rica, chlorpyrifos-treated bags are increasingly used to protect banana and plantain fruits from insects and to fulfill product standards, even in populated areas. OBJECTIVES To evaluate childrens exposure to chlorpyrifos in villages situated nearby banana plantations and plantain farms in Costa Rica. METHODS The study targeted two villages with use of chlorpyrifos-treated bags in nearby banana plantations and plantain farms and one village with mainly organic production. For 140 children from these villages, mostly indigenous Ngäbe and Bribri, parent-interviews and urine samples (n=207) were obtained. Urinary 3,5,6-trichloro-2-pyridinol (TCPy) levels were measured as a biomarker for chlorpyrifos exposure. In the banana and plantain village also environmental contamination to chlorpyrifos was explored. RESULTS Children from the banana and plantain villages had statistically significant higher urinary TCPy concentrations than children from the referent village; 2.6 and 2.2 versus 1.3μg/g creatinine, respectively. Chlorpyrifos was detected in 30% of the environmental samples as well as in 92% of the hand/foot wash samples. For more than half of the children their estimated intake exceeded the US EPA chronic population adjusted dose. For some, the acute population adjusted dose and the chronic reference dose were also exceeded. CONCLUSIONS Our results suggest that children living nearby plantations with chlorpyrifos-treated bags are exposed to chlorpyrifos levels that may affect their health. Interventions to reduce chlorpyrifos exposure are likely to improve childrens health and environment in banana and plantain growing regions.

Advancing the 3Rs in regulatory toxicology - Carcinogenicity testing: Scope for harmonisation and advancing the 3Rs in regulated sectors of the European Union.

Different government agencies operating in the European Union regulate different types of chemical products but all require testing for carcinogenicity to support applications for product marketing and commercialisation. A conference was held in Brussels in 2013 where representatives of the pharmaceutical, animal health, chemical and plant protection industries, together with representatives of regulatory agencies, universities and other stakeholders, met under the auspices of The European Partnership for Alternative Approaches to Animal Testing (EPAA) to discuss the varying requirements for carcinogenicity testing, and how these studies might be refined to improve hazard evaluation and risk assessment while implementing principles of the 3Rs (replacement, refinement and reduction in animal studies). While there are some similarities, the regulatory approaches in pharmaceutical, animal health, chemical and plant protection sectors have varying degrees of flexibility in requirements for carcinogenicity testing, to an extent reflecting concerns over the magnitude and duration of human exposure, either directly as in therapeutic exposure to pharmaceuticals, or indirectly through the ingestion of residues of veterinary drugs or plant protection chemicals. The article discusses these differences and other considerations for modified carcinogenicity testing paradigms on the basis of scientific and 3Rs approaches.

Discrepancy among acute guideline levels for emergency response.

Acute guidance values are tools for public health risk assessment and management during planning, preparedness and response related to sudden airborne release of hazardous chemicals. The two most frequently used values, i.e. Acute Exposure Guidance Levels (AEGL) and Emergency Response Planning Guideline (ERPG), were compared in qualitative and quantitative terms. There was no significant difference between the general level of AEGL and ERPG values, suggesting the two systems are equally precautious. However, the guidance values diverged by a factor of 3 or more for almost 40% of the substances, including many of high production volume. These deviations could be explained by differences in selection of critical effect or critical study and in a few cases differences in interpretation of the same critical study. Diverging guidance values may hamper proper risk communication and risk management. Key factors for broad international acceptance of harmonized values include transparency of the decision process, agreement on definition of toxicological tiers, and a target population including sensitive groups of the general population. In addition, development of purely health based values is encouraged. Risk management issues, such as land use and emergency response planning should be treated separately, as these rely on national legislation and considerations.

Benchmark dose approaches in chemical health risk assessment in relation to number and distress of laboratory animals.

Use of benchmark dose (BMD) approaches is expected to increase substantially, with growing awareness among researchers and inclusion in regulatory testing guidance documents such as REACH. The BMD approach has clear advantages over the No-Observed-Adverse-Effect-Level (NOAEL) approach in defining toxicological thresholds, risk levels, and points of departure as the basis for setting guidance and limit values. Several aspects of the BMD may increase the use of laboratory animals; the optimal number of dose groups for BMD calculation is between five and ten, rather than the current standard of four; also, experiments with more animals will result in narrow confidence intervals. However, this paper presents several counterarguments suggesting that design of experiments suited for BMD analyses might be used to decrease the distress and use of laboratory animals. If experiments are performed with unequal group size, with fewer animals in the high response dose groups and more animals close to toxicological threshold, the aggregated distress might be reduced. In addition, there is a need to evaluate how the total number of animals affects the quality of BMD (e.g. in terms of confidence intervals). Development of strategies for optimal design of experiments requires tools which evaluate experimental designs from an ethical perspective; a concept of distress-adjusted number of animals is suggested.

Toxicity of Bromkal 70-5DE, a technical mixture of polybrominated diphenyl ethers, following 28 d of oral exposure in rats and impact of analysed impurities.

The subacute toxicity of a commercial polybrominated diphenyl ether (PBDE) preparation, Bromkal 70-5DE, was investigated. In addition to a vehicle control, the mixture was given orally to male and female Sprague-Dawley rats for 28 d at three dose levels; 2.5, 25 and 250 mg kg(-1) b.w.d(-1). The observed effects include increased hepatic EROD activity (from 2.5 mg kg(-1)d(-1)); increased liver weight (males), increased PROD activity and depletion of hepatic retinoids (from 25 mg kg(-1)d(-1)); and increased liver weight (females), marked histological changes in the liver and lungs, as well as increased serum parameters such as total protein, cholesterol and albumin (from 250 mg kg(-1)d(-1)). Chemical analysis of the PBDE mixture with gas chromatography/mass spectrometry (GS/MS) showed impurities of polybrominated dibenzofurans and to a lesser extent dibenzodioxins, in total levels of about 7.0 microg g(-1) of Bromkal technical mixture. The animals were thereby exposed to an estimated dose of dioxin-like equivalents corresponding to 1.3-131 ng TEQ kg(-1) b.w.d(-1). It cannot be ruled out that this level of impurities can explain the hepatic EROD induction and hepatic retinoid depletion, which are considered typical markers of toxicity mediated via the aryl hydrocarbon receptor (AhR).