Risk assessment for handling hazardous substances within the European industry: Available methodologies and research streams.

After the Seveso disaster occurred more than 40 years ago, there has been an increasing awareness of the potential impacts that similar accident events can occur in a wide range of process establishments, where the handling and production of hazardous substances pose a real threat to society and the environment. In these industrial sites denominated "Seveso sites," the urgent need for an effective strategy emerged markedly to handle hazardous activities and to ensure safe conditions. Since then, the main challenging research issues have focused on how to prevent such accident events and how to mitigate their consequences leading to the development of many risk assessment methodologies. In recent years, researchers and practitioners have tried to provide useful overviews of the existing risk assessment methodologies proposing several reviews. However, these reviews are not exhaustive because they are either dated or focus only on one specific topic (e.g., liquefied natural gas, domino effect, etc.). This work aims to overcome the limitations of the current reviews by providing an up-to-date and comprehensive overview of the risk assessment methodologies for handling hazardous substances within the European industry. In particular, we have focused on the current techniques for hazards and accident scenarios identification, as well as probability and consequence analyses for both onshore and offshore installations. Thus, we have identified the research streams that have characterized the activities of researchers and practitioners over the years, and we have then presented and discussed the different risk assessment methodologies available concerning the research stream that they belong to.

Prenatal dioxin exposure and thyroid hormone levels in the Seveso second generation study.

BACKGROUND: In animal studies, perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters thyroid homoeostasis and thyroid hormone concentrations; epidemiologic evidence is limited. OBJECTIVES: We aimed to determine the association of prenatal exposure to TCDD with thyroid hormone concentrations in the Seveso Second Generation Study, a unique cohort of children born to TCDD-exposed women resulting from a 1976 chemical factory explosion in Seveso, Italy. METHODS: We included 570 children (288 female, 282 male) with complete follow-up data, including a fasting blood draw. Serum levels of total and free thyroxine (T4), free triiodothyronine (T3), and thyroid stimulating hormone (TSH) were measured using immunoassays. We defined prenatal TCDD exposure as: 1) maternal initial TCDD concentration measured in serum collected soon after the explosion and 2) maternal TCDD estimated at pregnancy. RESULTS: Compared to the lowest quartile (Q1), maternal initial serum TCDD was associated with lower free T3 (Q2: adj-ß = -0.13, 95%CI -0.26, 0.00; Q3: adj-ß = -0.22, 95%CI -0.35, -0.09; Q4: adj-ß = -0.14, 95%CI -0.28, 0.00; p-trend = 0.02). In participants with high thyroid antibody status, inverse associations between maternal initial serum TCDD and free T3 were significantly stronger than in participants with normal antibody status (p-interaction = 0.02). We also observed a positive association between maternal initial serum TCDD and TSH concentrations in participants with high thyroid antibody status (Q2: adj-ß = 11.4%, 95%CI -25.2, 66.1; Q3: adj-ß = 49.0%, 95%CI 3.0, 115.5; Q4: adj-ß = 105.5, 95%CI 36.6, 209.2; p-trend < 0.01) but not in those participants with normal antibody status (p-interaction < 0.01). Similar results were found for TCDD estimated at pregnancy. DISCUSSION: Our results suggest prenatal exposure to TCDD, a potent endocrine-disrupting compound, may alter thyroid function later in life. Populations with additional thyroid stress may be particularly susceptible to in utero exposure of thyroid disrupting chemicals.

Neurocognitive and physical functioning in the Seveso Women's Health Study.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is neurotoxic in animals but few studies have investigated its effects on the human brain. Related dioxin-like compounds have been linked to poorer cognitive and motor function in older adults, with effects more pronounced in women, perhaps due to the loss of neuro-protective estrogen in menopause. On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in one of the highest known residential exposures to TCDD. In 1996, we initiated the Seveso Women's Health Study, a retrospective cohort study of the health of the women who were newborn to 40 years old in 1976. Here, we investigate whether TCDD exposure is associated with physical functioning and working memory more than 20 years later. Individual TCDD concentration (ppt) was measured in archived serum collected soon after the explosion. In 1996 and 2008, we measured physical functioning (n=154) and working memory (n=459), respectively. We examined associations between serum TCDD and motor and cognitive outcomes with multivariate linear regression and semi-parametric estimators. A 10-fold increase in serum TCDD was not associated with walking speed (adjusted ß=0.0006ft/s, 95% Confidence Interval (CI): -0.13, 0.13), upper body mobility (adjusted ß=-0.06, 95% CI: -0.36, 0.23), or manual dexterity (adjusted ß=0.34, 95% CI: -0.65, 1.33). We observed an inverted U-shaped association in grip strength, with poorer strength in the lowest and highest TCDD exposure levels. There was no association between TCDD and the Wechsler digit and spatial span tests. Neither menopause status at assessment nor developmental timing of exposure modified associations between TCDD and working memory. Our findings, in one of the only studies of TCDD's effects on neuropsychological and physical functioning in women, do not indicate an adverse effect on these domains, with the exception of a U-shaped relationship with grip strength. Given the limited assessment and relative youth of the women at this follow-up, future work examining additional neuropsychological outcomes is warranted.

Prenatal exposure to TCDD and atopic conditions in the Seveso second generation: a prospective cohort study.

BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant that can bioaccumulate in humans, cross the placenta, and cause immunological effects in children, including altering their risk of developing allergies. On July 10, 1976, a chemical explosion in Seveso, Italy, exposed nearby residents to a high amount of TCDD. In 1996, the Seveso Women's Health Study (SWHS) was established to study the effects of TCDD on women's health. Using data from the Seveso Second Generation Health Study, we aim to examine the effect of prenatal exposure to TCDD on the risk of atopic conditions in SWHS children born after the explosion. METHODS: Individual-level TCDD was measured in maternal serum collected soon after the accident. In 2014, we initiated the Seveso Second Generation Health Study to follow-up the children of the SWHS cohort who were born after the explosion or who were exposed in utero to TCDD. We enrolled 677 children, and cases of atopic conditions, including eczema, asthma, and hay fever, were identified by self-report during personal interviews with the mothers and children. Log-binomial and Poisson regressions were used to determine the association between prenatal TCDD and atopic conditions. RESULTS: A 10-fold increase in 1976 maternal serum TCDD (log10TCDD) was not significantly associated with asthma (adjusted relative risk (RR) = 0.93; 95% CI: 0.61, 1.40) or hay fever (adjusted RR = 0.99; 95% CI: 0.76, 1.27), but was significantly inversely associated with eczema (adjusted RR = 0.63; 95% CI: 0.40, 0.99). Maternal TCDD estimated at pregnancy was not significantly associated with eczema, asthma, or hay fever. There was no strong evidence of effect modification by child sex. CONCLUSIONS: Our results suggest that maternal serum TCDD near the time of explosion is associated with lower risk of eczema, which supports other evidence pointing to the dysregulated immune effects of TCDD.

Human 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure and thyroid cancer risk.

Thyroid cancer incidence has been steadily rising since the 1970s and exposure to environmental pollutants, including persistent organic pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxins, has emerged as a potential explanation for this increase. This study aimed to summarize available human studies on the association between TCDD exposure and thyroid cancer. A systematic review of the literature was performed searching the National Library of Medicine and National Institutes of Health PubMed, Embase, and Scopus databases, through January 2022, using the following keywords: "thyroid", "2,3,7,8-tetrachlorodibenzo-p-dioxin", "TCDD", "dioxin", and "Agent Orange". Six studies were included in this review. Three studies evaluated the acute exposure to the chemical factory accident in Seveso, Italy, and found a non-significant increase in the risk of thyroid cancer. Two studies investigating Agent Orange exposure among United States Vietnam War veterans found a significant risk of thyroid cancer following exposure. No association was found in one study evaluating TCDD exposure through herbicides. The current study highlights the limited information on the potential association between TCDD exposure and thyroid cancer and thus the need for future human studies, especially considering the persistent human exposure to dioxins in the environment.

The Fallout of Catastrophic Technogenic Emissions of Toxic Gases Can Negatively Affect Covid-19 Clinical Course.

The coronavirus D-19 (Covid-19) pandemic has shaken almost every country in the world: as we stand, 6,3 million deaths from the infection have already been recorded, 167,000 and 380,000 of which are in Italy and the Russian Federation, respectively. In the first wave of the pandemic, Italy suffered an abnormally high death toll. A detailed analysis of available epidemiological data suggests that that rate was shockingly high in the Northern regions and in Lombardy, in particular, whilst in the southern region the situation was less dire. This inexplicably high mortality rate in conditions of a very well-developed health care system such as the one in Lombardy - recognized as one of the best in Italy - certainly cries for a convincing explanation. In 1976, the small city of Seveso, Lombardy, experienced a release of dioxin into the atmosphere after a massive technogenic accident. The immediate effects of the industrial disaster did not become apparent until a surge in the number of tumors in the affected population in the subsequent years. In this paper, we endeavor to prove our hypothesis that the release of dioxin was a negative cofactor that contributed to a worsening of the clinical course of COVID-19 in Lombardy.

Prenatal dioxin exposure and glucose metabolism in the Seveso Second Generation study.

BACKGROUND: Exposure to endocrine disrupting compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during susceptible developmental windows may alter risk of metabolic disease later in life. Animal studies of in utero and lactational TCDD exposure report associations with alterations in insulin sensitivity and energy homeostasis, but epidemiologic evidence is limited. We examined the relationship of prenatal TCDD exposure with markers of glucose homeostasis in the Seveso Second Generation study, a unique cohort of children born to TCDD-exposed women resulting from a 1976 explosion in Seveso, Italy. METHODS: We included 426 children who were 18 years or older with complete follow-up data including a fasting blood draw. Insulin and glucose were measured and the updated homoeostatic model assessment was used to estimate insulin resistance (HOMA2-IR) and beta-cell function (HOMA2-B). Prenatal TCDD exposure was defined in two ways, as initial maternal serum TCDD concentration and TCDD estimated at pregnancy. RESULTS: The children (222 female, 204 male) averaged 28.6 (±6.0) years. We found a 10-fold increase in TCDD estimated at pregnancy was inversely associated with insulin (adj-ß = -1.24 µIU/mL, 95% confidence interval (CI): -2.38, -0.09) and HOMA2-B (adj-ß = -10.2% decrease, 95% CI: -17.8, -1.9) among daughters, but not sons (insulin: adj-ß = 0.57 µIU/mL, 95% CI: -0.84, 1.98, P for interaction = 0.04; and HOMA2-B: adj-ß = 0.8% increase, 95% CI -10.7, 13.9, P for interaction = 0.11). Similar effect modification was observed for TCDD estimated at pregnancy and HOMA2-IR (P for interaction = 0.13). The models for initial maternal serum TCDD showed similar effect modification by child sex. The observed associations in daughters showed evidence of mediation by body mass index, which we have previously found to be associated with prenatal TCDD exposure in female offspring. CONCLUSION: These results suggest prenatal exposure to TCDD is associated with lower insulin resistance and beta compensation in female offspring, and show evidence of mediation by body mass index.

Age at menarche in Seveso daughters exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with delayed pubertal development in animal studies. No epidemiologic study has investigated this association. We examined the relationship of in utero exposure to TCDD with reported age at onset of menarche in female children born to a unique cohort of TCDD-exposed women resulting from an explosion in Seveso, Italy, on 10 July 1976. METHODS: In 2014, nearly 40 years after the explosion, we enrolled postexplosion offspring, 2 to 39 years of age, in the Seveso Second Generation Study. Age at onset of menarche (years) was collected for 316 daughters by maternal report or self-report at interview. In utero TCDD exposure was defined by maternal TCDD serum concentrations extrapolated to the pregnancy. RESULTS: At interview, 287 daughters were postmenarche and reported age at menarche averaged 12.1 years (±1.3 years). Overall, we found no change in risk of menarche onset with a 10-fold increase in in utero TCDD exposure (hazard ratio [HR] = 0.86; 95% confidence interval [CI] = 0.71, 1.04). When we considered maternal menarche status in 1976 as a potentially sensitive developmental exposure window, in utero TCDD (log10) was associated with later age at menarche among daughters whose mothers were premenarche (HR = 0.71; 95% CI = 0.52, 0.97) but not postmenarche (HR = 0.89; 95% CI = 0.71, 1.12) at the time of the explosion (P int = 0.24). CONCLUSIONS: These results suggest that in utero TCDD exposure may alter pubertal timing among daughters of women who were prepubescent at the time of the Seveso accident.

Improving Education and Training of Dutch Major Hazard Control Inspectors: A 15 Years Longitudinal Case Study.

The education and training program for inspectors of Major Accident Hazard Establishments, specifically the EC Seveso III directive implicated Dutch chemical companies, changed considerably over a fifteen year period. This longitudinal, time-series cross sectional case study describes the development of the education and training program for Major Hazard Control inspectors, acting as regulators from the Labour inspectorate, belonging to the Dutch Ministry of Social Affairs and Employment. A blueprint had to be constructed in order to assess the development and quality of this program in four cross sections over time. The description highlights both the safety related content and the regulator skills parts of the program in its changing context. Professional standards, educational objectives, quality of education, evaluation method, education change process and the response to the dynamic operational environment were examined. The main findings are that the education and training program kept the same main structure over the time period while its contents were adapted to respond to external context changes. Internal evaluation of performance data and education style led to a shift in contents from theoretical knowledge towards safety management and inspection practice oriented experience related knowledge. An active teaching style, increased usage of professional standards and more systematic evaluation, starting from the blue print in this study, offer the best opportunities for further improvement. Current insights on regulatory performance lead to a recommended future perspective for the inspectors' role to be translated into education and training: balancing empathy, inquisitiveness and support with control and enforcement, or rather: exert tough love, staying between too soft and too hard.

Prenatal dioxin exposure and neuropsychological functioning in the Seveso Second Generation Health Study.

BACKGROUND: Prenatal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure has been shown to alter sexual differentiation of the brain in animal models, impacting pubertal development, behavior, cortical dominance, and cognition. The effects of early life exposure to dioxin-like compounds on human neurodevelopment, however, are less clear and warrant further investigation. METHODS: The Seveso Women's Health Study (SWHS), initiated in 1996, is a well-characterized cohort of 981 Italian women who lived in proximity to an industrial accident in July 1976 that resulted in one of the highest residential TCDD exposures on record. In 2014-2016, we enrolled offspring born after the accident into the Seveso Second Generation Health Study. Children aged 7-17 years old (n = 161) completed a neuropsychological assessment spanning executive function and reverse learning (Wisconsin Card Sort), non-verbal intelligence (Raven's Progressive Matrices), attention and hyperactivity (Connor's Continuous Performance (CPT), and memory (Rey's Auditory Verbal Learning). We used multivariate regression with robust standard error estimates accounting for clustering of siblings to model the associations between these outcomes and prenatal exposure defined as TCDD measured in maternal serum collected soon after the explosion and estimated to pregnancy. RESULTS: The children (82 male, 79 female) averaged 13.1 (±2.9) years of age. Adjusting for covariates, a 10-fold increase in maternal serum TCDD was not adversely associated with reverse learning/set-shifting, memory, attention/impulsivity, or non-verbal intelligence. In sex-stratified models, prenatal TCDD was associated with more non-perseverative errors in boys but not in girls (pint = 0.04). TCDD was also associated with attention deficits on the CPT but only among children with the shortest breastfeeding histories. CONCLUSIONS: While overall, there were no significant associations, the observed differential neurotoxic sensitivities to TCDD by sex and lactation history may warrant confirmation in future studies.

The Seveso accident: A look at 40 years of health research and beyond.

A 1976 chemical factory explosion near Seveso, Italy exposed residents to high levels of 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD or dioxin). Dioxin is a known human carcinogen and potent endocrine disruptor. It is highly lipophilic and has a long half-life in humans. Much of what we know and can learn about the risks of dioxin exposure on human health arose from the tragic circumstances of Seveso. This review aims to describe the Seveso accident, summarize the results of 40 years of research on the health of the Seveso population since the accident, and discuss next-stage research on the health of Seveso residents, their children, and grandchildren.

Maternal dioxin exposure and pregnancy outcomes over 30 years of follow-up in Seveso.

Animal evidence suggests an association between exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and adverse pregnancy outcomes. Epidemiologic studies report inconsistent results, but are limited by narrow range of exposure, small sample size, and lack of a biologic measure of highest lifetime exposure. On July 10, 1976, a chemical explosion in Seveso, Italy resulted in the highest known residential exposure to TCDD. In 1996, we initiated the Seveso Women's Health Study (SWHS), a retrospective cohort of TCDD exposure and reproductive health. Individual-level TCDD was measured in serum collected soon after the explosion. After 20years of follow-up, we found no association between maternal TCDD in 1976 serum or estimated at pregnancy and spontaneous abortion (SAB), fetal growth, or gestational length. Here, we present an updated analysis of TCDD exposure and adverse pregnancy outcomes from a subsequent follow-up of the SWHS cohort in 2008-2009. SWHS women had 1211 post-explosion pregnancies through the 2008-2009 follow-up. We found no association between TCDD estimated at pregnancy and SAB, fetal growth, or gestational length. However, we found a non-significant inverse association between maternal 1976 serum TCDD and birthweight (adjusted ß=-22.8, 95% CI: -80.1, 34.6). The association was stronger among first post-explosion births, but remained non-significant (adjusted ß=-47.7, 95% CI: -107.3, 11.9). SWHS is the first study to be able to consider two potentially relevant measures of TCDD exposure: highest lifetime dose and in utero. Our results, although non-significant, suggest that highest dose may be more relevant in epidemiologic studies of TCDD and pregnancy outcomes.