Jouni T. Tuomisto

Flame retardants in placenta and breast milk and cryptorchidism in newborn boys

Background Polybrominated diphenyl ethers (PBDEs) are widely used in Western countries. Objectives Because the prevalence of cryptorchidism appears to be increasing, we investigated whether exposure to PBDEs was associated with testicular maldescent. Methods In a prospective Danish–Finnish study, 1997–2001, all boys were examined for cryptorchidism. We analyzed whole placentas (for 95 cryptorchid/185 healthy boys) and individual breast milk samples (62/68) for 14 PBDEs and infant serum samples for gonadotropins, sex-hormone binding globulin, testosterone, and inhibin B. Results In 86 placenta–milk pairs, placenta PBDE concentrations in fat were lower than in breast milk, and a larger number of congeners were nondetectable. There was no significant difference between boys with and without cryptorchidism for individual congeners, the sum of 5 most prevalent, or all 14 congeners. The concentration of PBDEs in breast milk was significantly higher in boys with cryptorchidism than in controls (sum of BDEs 47, 153, 99, 100, 28, 66, and 154: median, 4.16 vs. 3.16 ng/g fat; p < 0.007). There was a positive correlation between the sum of PBDEs and serum luteinizing hormone (p < 0.033). The sum of PBDEs in breast milk did not differ between Denmark and Finland (median, 3.52 vs. 3.44 ng/g fat), but significant differences in some individual congeners were found. Conclusions Two different proxies were used for prenatal PBDE exposure, and levels in breast milk, but not in placenta, showed an association with congenital cryptorchidism. Other environmental factors may contribute to cryptorchidism. Our observations are of concern because human exposure to PBDEs is high in some geographic areas.

Improving health through policies that promote active travel: A review of evidence to support integrated health impact assessment

BACKGROUND Substantial policy changes to control obesity, limit chronic disease, and reduce air pollution emissions, including greenhouse gasses, have been recommended. Transportation and planning policies that promote active travel by walking and cycling can contribute to these goals, potentially yielding further co-benefits. Little is known, however, about the interconnections among effects of policies considered, including potential unintended consequences. OBJECTIVES AND METHODS We review available literature regarding health impacts from policies that encourage active travel in the context of developing health impact assessment (HIA) models to help decision-makers propose better solutions for healthy environments. We identify important components of HIA models of modal shifts in active travel in response to transport policies and interventions. RESULTS AND DISCUSSION Policies that increase active travel are likely to generate large individual health benefits through increases in physical activity for active travelers. Smaller, but population-wide benefits could accrue through reductions in air and noise pollution. Depending on conditions of policy implementations, risk tradeoffs are possible for some individuals who shift to active travel and consequently increase inhalation of air pollutants and exposure to traffic injuries. Well-designed policies may enhance health benefits through indirect outcomes such as improved social capital and diet, but these synergies are not sufficiently well understood to allow quantification at this time. CONCLUSION Evaluating impacts of active travel policies is highly complex; however, many associations can be quantified. Identifying health-maximizing policies and conditions requires integrated HIAs.

Effects of 2,3,7,8‐Tetrachlorodibenzo‐p‐Dioxin on Bone in Two Rat Strains with Different Aryl Hydrocarbon Receptor Structures

Polychlorinated dibenzo‐p‐dioxins (PCDDs) are highly toxic environmental contaminants, and 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) is the most potent dioxin. Here, we studied the effects of TCDD on bone. Two rat strains, Han/Wistar (H/W) and Long‐Evans (L‐E), were used because they exhibit a 1000‐fold sensitivity difference in acute lethality of TCDD, which difference is related to the aryl hydrocarbon receptor (AHR). TCDD inhibited the tibial growth dose dependently, the effect being manifested at lower doses in the more sensitive L‐E strain. In H/W rats the effect of TCDD was seen only at the high dose of 170 μg/kg (p < 0.05), whereas in the sensitive L‐E rats a significant reduction of bone growth was already seen at 1.7 μg/kg (p < 0.01). This reduction was caused by the smaller tibial size because the diaphyseal bone mineral density (BMD) did not change. The three‐point bending breaking force of the tibia was significantly reduced in H/W rats at 170 μg/kg (p < 0.05), but tibial stiffness was lower already at the dose of 17 μg/kg (p < 0.05). In the sensitive L‐E strain, both breaking force and stiffness were reduced at the dose of 17 μg/kg (p < 0.001). These results indicate that TCDD dose‐dependently interferes with bone growth, modeling, and mechanical strength. The altered transactivation domain of AHR is associated with a lower sensitivity of bone to TCDD in H/W rats, suggesting that AHR plays a role in modulating the effects of dioxins on bone.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on liver phosphoenolpyruvate carboxykinase (PEPCK) activity, glucose homeostasis and plasma amino acid concentrations in the most TCDD-susceptible and the most TCDD-resistant rat strains.

Abstract Reduced gluconeogenesis due to decreased activity of key gluconeogenic enzymes in liver, together with feed refusal, has been suggested to play an important role in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced lethality in rats. This study was carried out to further analyse the toxicological significance of reduced gluconeogenesis by comparing dose-responses and time-courses of effects of TCDD on the activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver, liver glycogen concentration as well as plasma concentrations of glucose and amino acids in both genders of TCDD-sensitive Long-Evans (L-E) rats and TCDD-resistant Han/Wistar (H/W) rats. A dose-dependent decrease in PEPCK activity was observed in H/W rats, but in L-E rats the activity was not decreased. However, TCDD impaired the strong increase in liver PEPCK activity observed in pair-fed controls of the L-E strain. Liver glycogen concentrations were severely decreased in L-E rats and moderately in H/W rats. This effect seems to be secondary to reduced feed intake, since a similar decrease was seen in pair-fed controls. Decreases in plasma glucose concentrations were also more profound in L-E rats than in H/W rats, but pair-fed controls were generally less affected. Circulating concentrations of amino acids were markedly increased in TCDD-treated L-E rats, which is likely to reflect increased mobilization of amino acids and their decreased metabolism in liver. Reduction of liver PEPCK activity cannot account for the sensitivity difference of these two strains of rats in terms of mortality. Nevertheless, the response of both strains of TCDD-treated rats regarding gluconeogenesis is different from that seen in pair-fed controls and suggesting that impairment of this pathway contributes to the development of the wasting syndrome.

Soft‐tissue sarcoma and dioxin: A case‐control study

Soft‐tissue sarcoma has been proposed to be a candidate for a dioxin‐induced cancer. However, previous epidemiologic studies have suffered from poor exposure data and mixed exposures. We studied the association between sarcoma risk and individually estimated dioxin exposure in a general population exposed to relatively low levels of dioxin via food. A multicenter prospective case‐control study was conducted in 4 university hospitals and 12 other hospitals in southern Finland. Participants included 110 patients with soft‐tissue sarcoma (cases) and 227 area‐ and age‐matched controls. Controls were patients operated for appendicitis. Individual dioxin concentrations were analyzed from subcutaneous fat samples by gas chromatography‐mass spectrometry. The average (range) dioxin concentration was 33.4 (4.4–145.5) ng/kg (toxic equivalencies in fat according to WHO). No increased risk associated with increased dioxin concentration was observed. In contrast, the highest risk of sarcoma was found at low levels of dioxin. Odds ratios for different quintiles as compared with the lowest quintile of dioxins (median, 11.5 ng/kg) varied from 0.43 (95% CI = 0.18–1.05) to 0.65 (95% CI = 0.22–1.95). The result was little affected by studied confounders and the findings were similar for different sarcoma subtypes, age groups and study areas. The results imply that dioxin does not increase the risk of soft‐tissue sarcoma at the present population levels.

Health Effects Caused by Primary Fine Particulate Matter (PM2.5) Emitted from Buses in the Helsinki Metropolitan Area, Finland

Fine particle (PM(2.5)) emissions from traffic have been associated with premature mortality. The current work compares PM(2.5)-induced mortality in alternative public bus transportation strategies as being considered by the Helsinki Metropolitan Area Council, Finland. The current bus fleet and transportation volume is compared to four alternative hypothetical bus fleet strategies for the year 2020: (1) the current bus fleet for 2020 traffic volume, (2) modern diesel buses without particle traps, (3) diesel buses with particle traps, and (4) buses using natural gas engines. The average population PM(2.5) exposure level attributable to the bus emissions was determined for the 1996-1997 situation using PM(2.5) exposure measurements including elemental composition from the EXPOLIS-Helsinki study and similar element-based source apportionment of ambient PM(2.5) concentrations observed in the ULTRA study. Average population exposure to particles originating from the bus traffic in the year 2020 is assumed to be proportional to the bus emissions in each strategy. Associated mortality was calculated using dose-response relationships from two large cohort studies on PM(2.5) mortality from the United States. Estimated number of deaths per year (90% confidence intervals in parenthesis) associated with primary PM(2.5) emissions from buses in Helsinki Metropolitan Area in 2020 were 18 (0-55), 9 (0-27), 4 (0-14), and 3 (0-8) for the strategies 1-4, respectively. The relative differences in the associated mortalities for the alternative strategies are substantial, but the number of deaths in the lowest alternative, the gas buses, is only marginally lower than what would be achieved by diesel engines equipped with particle trap technology. The dose-response relationship and the emission factors were identified as the main sources of uncertainty in the model.

Uncertainty in mortality response to airborne fine particulate matter: Combining European air pollution experts

The authors have performed a structured expert judgment study of the population mortality effects of fine particulate matter (PM2.5) air pollution. The opinions of six European air pollution experts were elicited. The ability of each expert to probabilistically characterize uncertainty was evaluated using 12 calibration questions -- relevant variables whose true values were unknown at the time of elicitation, but available at the time of analysis. The elicited opinions exhibited both uncertainty and disagreement. It emerged that there were significant differences in expert performance. Two combinations of the experts’ judgments were computed and evaluated -- one in which each expert’s views received equal weight; the other in which the expert’s judgments were weighted by their performance on the calibration variables. When the performance of these combinations was evaluated the equal-weight decision-maker exhibited acceptable performance, but was nonetheless inferior to the performance-based decision-maker. In general, the experts agreed with published studies for the best estimate of all-cause mortality from PM2.5; however, as would be expected, they gave confidence intervals that were several times broader than the statistical confidence intervals taken directly from the most frequently cited published studies. The experts were rather comfortable with applying epidemiological results from one geographic region to another. However, there was more uncertainty and disagreement about issues of timing of the effect and about the relative toxicity of different constituents of PM2.5. Even so, the experts were in fairly good agreement that an appreciable fraction of the long-term health effects occurs within a few months from the exposure and that combustion-derived particles are more toxic than PM2.5 on average, while secondary sulphates, nitrates and/or crustal materials may be less toxic. These assessments bring very valuable and relevant information to air pollution risk assessment.

Dose-response analysis of short-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in three differentially susceptible rat lines.

Line A, B, and C rats were selectively bred from TCDD-resistant Han/Wistar (Kuopio; H/W) and TCDD-sensitive Long-Evans (Turku/AB; L-E) rats. Line A rats are the most resistant to TCDD acute lethality followed by line B and line C rats. The resistance in line A rats is associated with a mutated H/W-type aryl hydrocarbon receptor (Ahr) allele (Ahr(hw)) and in line B rats the resistance is associated with an allele of an unknown gene B (B(hw)), while line C rats are almost as sensitive to TCDD as L-E rats. The dose-responses of characteristic short-term effects (day 8 postexposure) of TCDD were used to evaluate the efficacy (magnitude of effect) and potency relationships between these lines. Line A rats showed similar efficacies as line C (line A:line C efficacy ratio more than 0.7) for thymus weight, EROD activity, and incisor tooth defects. In contrast, efficacies in line A were decreased (efficacy ratios 0.19-0.37) for body weight change, serum bilirubin, and FFA levels, and serum ASAT activity. For most endpoints the efficacies in line B rats seem to be lower than in line C rats. The potencies were close to each other in line A and B rats, but somewhat lower than in line C rats. The results support our previous concept of two different AHR-mediated signaling pathways leading to dioxin type I and type II endpoints. Rats with the Ahr(hw/hw) genotype show a markedly decreased efficacy for type II endpoints, but B(hw) allele had only a minor effect on efficacies for most endpoints. Both H/W-type resistance alleles also decreased the potency of TCDD. However, the potency differences in short-term toxicity seem not to explain, at least alone, the differences seen in acute lethality among the rat lines.

2,3,7,8-tetrachlorodibenzo-p-dioxin-induced anorexia and wasting syndrome in rats: aggravation after ventromedial hypothalamic lesion

Long-term regulation of body weight and food intake were studied after rats were subjected to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which causes hypophagia and body weight loss, and to ventromedial hypothalamic lesion, which causes hyperphagia, metabolic changes and obesity. These two factors appeared to have an interaction, as ventromedial hypothalamic lesion initially aggravated the effects of TCDD on body weight and food intake. This was seen in both TCDD-resistant and TCDD-susceptible rat strains. In contrast, if TCDD was given several weeks before the lesion and body weight had stabilized to a low level, no aggravation was seen, but TCDD completely blocked the effects of ventromedial hypothalamic lesion. Thus, TCDD seems to affect the same regulation chain that is involved in the lesioning of the ventromedial hypothalamus. TCDD might serve as a tool in studying different mechanisms of long-term food intake and body weight regulation.

Comparison of acute toxicities of indolo[3,2-b]carbazole (ICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons are environmental toxicants that act via the AH receptor (AHR). In vitro studies have demonstrated that some indole derivatives present in cruciferous vegetables also bind to the AHR. One of the highest AHR binding affinities is exhibited by indolo[3,2-b]carbazole (ICZ). Since exposure to these dietary indoles is quantitatively far larger than that to halogenated aromatic compounds, their potential toxic risks have raised concern. In the present study, we compared the effects of ICZ with those of a single dose of 20 microg/kg TCDD in the most TCDD-sensitive rat strain (Long-Evans [Turku AB]) (L-E). Whereas TCDD elicited the expected toxicity syndrome, ICZ, either as a single subcutaneous dose (63.5, 127 or 508 microg/kg) or with repeated sc dosing (508 microg/kg for 5 days) failed to reproduce any toxic impacts of TCDD. Furthermore, a simultaneous ICZ treatment (63.5 or 127 microg/kg for 10 days) did not interfere with TCDD (20 microg/kg; single exposure) action. A moderate hepatic induction of CYP1A1 could be triggered by repeated intragastric administration of ICZ (127 microg/kg for 4 days, the last treatment 2.5 h prior to termination). In control experiments in a reconstituted yeast system, ICZ potently and dose-dependently activated L-E rat AHR function demonstrating that it represents a bona fide high-affinity ligand for the rat receptor in vivo. Thus, the present study does not support the view that dietary exposure to ICZ would present a hazard of AHR-mediated adverse health effects to humans.