PFASs-restriction proposal commentary on ECHA's Annex XV restriction report, proposal for a restriction, March 2023.

PFASs are defined as substances that contain at least one fully fluorinated methyl (CF3-) or methylene (-CF2-) carbon atom. The excellent technical properties of members of the PFAS group have led to their use in a wide range of applications. The substance group comprises more than 10,000 individual compounds. A variety of adverse effects has been described for single substances. For the majority of the PFASs, neither toxicokinetic data nor effect data is available. Hence, because of the small number of PFASs for which a full toxicological profile is available, grouping based on the existing data is not feasible. A critical problem of PFASs and their degradation products is the very high persistence, which clearly fulfils the criterion for the substance property Very Persistent (vP) according to Annex XIII of the REACH Regulation. Because of this property the European Commission is planning to take action. Defining suitable subgroups appears to be a scientifically based approach. However, to reach this goal, large data gaps would have to be closed which would take up to centuries, a time-frame, which is not defendable with respect to potential irreversible harm. Because of the time pressure resulting from the potential irreversible harm, the precautionary principle has been selected as an appropriate tool to handle PFASs and in the restriction proposal PFASs are treated as one group. This approach is justified in the view of the advisory committee of the German Society for Toxicology. ECHA's proposal received a lot of attention in the public. However, communication so far has obviously led to the misunderstanding of a proven health hazard for all PFASs. Communication should explain the justification of the broad inclusion of substances as being based on the precautionary principle. Data gaps versus current knowledge need to be clearly communicated; communication should also include the possibility for derogation of essential use. It should address the issue of suitable substitutes to avoid unintended health consequences; and it should mention that existing persistent environmental contamination calls for developing innovation in remediation techniques.

Long-term simulation of lead concentrations in agricultural soils in relation to human adverse health effects.

Lead (Pb) exposure of consumers and the environment has been reduced over the past decades. Despite all measures taken, immission of Pb onto agricultural soils still occurs, with fertilizer application, lead shot from hunting activities, and Pb from air deposition representing major sources. Little is known about the intermediate and long-term consequences of these emissions. To gain more insight, we established a mathematical model that considers input from fertilizer, ammunition, deposition from air, uptake of Pb by crops, and wash-out to simulate the resulting Pb concentrations in soil over extended periods. In a further step, human oral exposure by crop-based food was simulated and blood concentrations were derived to estimate the margin of exposure to Pb-induced toxic effects. Simulating current farming scenarios, a new equilibrium concentration of Pb in soil would be established after several centuries. Developmental neurotoxicity represents the most critical toxicological effect of Pb for humans. According to our model, a Pb concentration of ~ 5 mg/kg in agricultural soil leads to an intake of approximately 10 µg Pb per person per day by the consumption of agricultural products, the dose corresponding to the tolerable daily intake (TDI). Therefore, 5 mg Pb/kg represents a critical concentration in soil that should not be exceeded. Starting with a soil concentration of 0.1 mg/kg, the current control level for crop fields, our simulation predicts periods of ~ 50 and ~ 175 years for two Pb immission scenarios for mass of Pb per area and year [scenario 1: ~ 400 g Pb/(ha × a); scenario 2: ~ 175 g Pb/(ha × a)], until the critical concentration of ~ 5 mg/kg Pb in soil would be reached. The two scenarios, which differ in their Pb input via fertilizer, represent relatively high but not unrealistic Pb immissions. From these scenarios, we calculated that the annual deposition of Pb onto soil should remain below ~ 100 g/(ha × a) in order not to exceed the critical soil level of 5 mg/kg. We propose as efficient measures to reduce Pb input into agricultural soil to lower the Pb content of compost and to use alternatives to Pb ammunition for hunting.

Critical evaluation of human health risks due to hydraulic fracturing in natural gas and petroleum production.

The use of hydraulic fracturing (HF) to extract oil and natural gas has increased, along with intensive discussions on the associated risks to human health. Three technical processes should be differentiated when evaluating human health risks, namely (1) drilling of the borehole, (2) hydraulic stimulation, and (3) gas or oil production. During the drilling phase, emissions such as NOx, NMVOCs (non-methane volatile organic compounds) as precursors for tropospheric ozone formation, and SOx have been shown to be higher compared to the subsequent phases. In relation to hydraulic stimulation, the toxicity of frac fluids is of relevance. More than 1100 compounds have been identified as components. A trend is to use fewer, less hazardous and more biodegradable substances; however, the use of hydrocarbons, such as kerosene and diesel, is still allowed in the USA. Methane in drinking water is of low toxicological relevance but may indicate inadequate integrity of the gas well. There is a great concern regarding the contamination of ground- and surface water during the production phase. Water that flows to the surface from oil and gas wells, so-called 'produced water', represents a mixture of flow-back, the injected frac fluid returning to the surface, and the reservoir water present in natural oil and gas deposits. Among numerous hazardous compounds, produced water may contain bromide, arsenic, strontium, mercury, barium, radioactive isotopes and organic compounds, particularly benzene, toluene, ethylbenzene and xylenes (BTEX). The sewage outflow, even from specialized treatment plants, may still contain critical concentrations of barium, strontium and arsenic. Evidence suggests that the quality of groundwater and surface water may be compromised by disposal of produced water. Particularly critical is the use of produced water for watering of agricultural areas, where persistent compounds may accumulate. Air contamination can occur as a result of several HF-associated activities. In addition to BTEX, 20 HF-associated air contaminants are group 1A or 1B carcinogens according to the IARC. In the U.S., oil and gas production (including conventional production) represents the second largest source of anthropogenic methane emissions. High-quality epidemiological studies are required, especially in light of recent observations of an association between childhood leukemia and multiple myeloma in the neighborhood of oil and gas production sites. In conclusion, (1) strong evidence supports the conclusion that frac fluids can lead to local environmental contamination; (2) while changes in the chemical composition of soil, water and air are likely to occur, the increased levels are still often below threshold values for safety; (3) point source pollution due to poor maintenance of wells and pipelines can be monitored and remedied; (4) risk assessment should be based on both hazard and exposure evaluation; (5) while the concentrations of frac fluid chemicals are low, some are known carcinogens; therefore, thorough, well-designed studies are needed to assess the risk to human health with high certainty; (6) HF can represent a health risk via long-lasting contamination of soil and water, when strict safety measures are not rigorously applied.

[Four years after the Ebola crisis : Challenges, experiences, and implications in the German public health context]. / Vier Jahre nach der Ebolakrise : Herausforderungen, Erfahrungen und Schlussfolgerungen für den Öffentlichen Gesundheitsdienst in Deutschland.

The Ebola virus disease outbreak in West Africa in 2014/2015 was by far the biggest, most prolonged, and geographically most widespread outbreak of this disease since the discovery of the Ebola virus in 1976. Although no cases of Ebola virus disease were confirmed in Germany, a number of crisis management activities were initiated.Based on a combination of local, national, and international lessons learned, literature research, and a large number of discussions among German colleagues as well as German and foreign colleagues, the experiences of selected German public health actors as well as implications for health protection activities in Germany are presented.On the one hand, preparedness for managing unusual high consequence health events-caused by rare, highly pathogenic biological agents-including the provision of adequate material and personnel resources remains important in Germany. On the other hand, more German engagement in global health is necessary, because the dividing line between global health and local health is increasingly disappearing.

High exposure to inorganic arsenic by food: the need for risk reduction.

Arsenic is a human carcinogen that occurs ubiquitously in soil and water. Based on epidemiological studies, a benchmark dose (lower/higher bound estimate) between 0.3 and 8 µg/kg bw/day was estimated to cause a 1 % increased risk of lung, skin and bladder cancer. A recently published study by EFSA on dietary exposure to inorganic arsenic in the European population reported 95th percentiles (lower bound min to upper bound max) for different age groups in the same range as the benchmark dose. For toddlers, a highly exposed group, the highest values ranged between 0.61 and 2.09 µg arsenic/kg bw/day. For all other age classes, the margin of exposure is also small. This scenario calls for regulatory action to reduce arsenic exposure. One priority measure should be to reduce arsenic in food categories that contribute most to exposure. In the EFSA study the food categories 'milk and dairy products,' 'drinking water' and 'food for infants' represent major sources of inorganic arsenic for infants and also rice is an important source. Long-term strategies are required to reduce inorganic arsenic in these food groups. The reduced consumption of rice and rice products which has been recommended may be helpful for a minority of individuals consuming unusually high amounts of rice. However, it is only of limited value for the general European population, because the food categories 'grain-based processed products (non rice-based)' or 'milk and dairy products' contribute more to the exposure with inorganic arsenic than the food category 'rice.' A balanced regulatory activity focusing on the most relevant food categories is required. In conclusion, exposure to inorganic arsenic represents a risk to the health of the European population, particularly to young children. Regulatory measures to reduce exposure are urgently required.

Manufactured nanomaterials: categorization and approaches to hazard assessment.

Nanotechnology offers enormous potential for technological progress. Fortunately, early and intensive efforts have been invested in investigating toxicology and safety aspects of this new technology. However, despite there being more than 6,000 publications on nanotoxicology, some key questions still have to be answered and paradigms need to be challenged. Here, we present a view on the field of nanotoxicology to stimulate the discussion on major knowledge gaps and the critical appraisal of concepts or dogma. First, in the ongoing debate as to whether nanoparticles may harbour a specific toxicity due to their size, we support the view that there is at present no evidence of 'nanospecific' mechanisms of action; no step-change in hazard was observed so far for particles below 100 nm in one dimension. Therefore, it seems unjustified to consider all consumer products containing nanoparticles a priori as hazardous. Second, there is no evidence so far that fundamentally different biokinetics of nanoparticles would trigger toxicity. However, data are sparse whether nanoparticles may accumulate to an extent high enough to cause chronic adverse effects. To facilitate hazard assessment, we propose to group nanomaterials into three categories according to the route of exposure and mode of action, respectively: Category 1 comprises nanomaterials for which toxicity is mediated by the specific chemical properties of its components, such as released ions or functional groups on the surface. Nanomaterials belonging to this category have to be evaluated on a case-by-case basis, depending on their chemical identity. Category 2 focuses on rigid biopersistent respirable fibrous nanomaterials with a specific geometry and high aspect ratio (so-called WHO fibres). For these fibres, hazard assessment can be based on the experiences with asbestos. Category 3 focuses on respirable granular biodurable particles (GBP) which, after inhalation, may cause inflammation and secondary mutagenicity that may finally lead to lung cancer. After intravenous, oral or dermal exposure, nanoscaled GBPs investigated apparently did not show 'nanospecific' effects so far. Hazard assessment of GBPs may be based on the knowledge available for granular particles. In conclusion, we believe the proposed categorization system will facilitate future hazard assessments.

Concept for the Evaluation of Carcinogenic Substances in Population-Based Human Biomonitoring.

The Human Biomonitoring (HBM) Commission at the German Environment Agency holds the opinion that for environmental carcinogens for which no exposure levels can be assumed and are harmless to health, health-based guidance values corresponding to the classical definition of the HBM-I or HBM-II value cannot be established. Therefore, only reference values have been derived so far for genotoxic carcinogens from exposure data of the general population or subpopulations. The concept presented here opens up the possibility of performing health risk assessments of carcinogenic substances in human biomonitoring, and thus goes decisively beyond the purely descriptive statistical reference value concept. Using the presented method, quantitative dose descriptors of internal exposure can be derived from those of external exposure, provided that sufficient toxicokinetic information is available. Dose descriptors of internal exposure then allow the simple estimate of additional lifetime cancer risks for measured biomarker concentrations or, conversely, of equivalent concentrations for selected risks, such as those considered as tolerable for the general population. HBM data of chronic exposures to genotoxic carcinogens can thus be used to assess the additional lifetime cancer risk referring to the general population and to justify and prioritize risk management measures.

A systematic review of experimental animal studies on microbial bioaerosols: Dose-response data for the derivation of exposure limits.

Although exposure to high levels of microbial bioaerosols can be linked to the deterioration of the human respiratory system, precise exposure levels responsible for such effects are still unknown. A previous systematic review concluded that there was not enough information in the studies in humans to derive an exposure-response relationship. Thus, the aim of this systematic review was to derive exposure limits for microbial bioaerosols based on health effects in experimental animal studies. A systematic search was done in MEDLINE (PubMed) for long-term in vivo exposure of the respiratory system via inhalation of a quantified microbial bioaerosol. A total of n = 301 studies were retrieved. Abstract screening using predefined inclusion and exclusion criteria was followed by full-text screening and standardized data extraction of study characteristics and measured outcomes. As a result, four suitable studies were identified where mice or guinea pigs were exposed for 4-12 weeks to a previously described mixture of fungal spores or conidia via inhalation. The number of macrophages, neutrophils, eosinophils and lymphocytes following subchronic exposure has been reported by all included papers and suggested a dose- and time-dependent relationship. Significant inflammation was observed following subacute exposure to Aspergillus fumigatus. However, the outcomes of the studies could not be directly compared due to the large degree of variation and poor description of the exposure conditions. It is our conclusion that more experimental research needs to be done with the specific aim of establishing a No-Observed-Adverse-Effect Level (NOAEL) and a Lowest-Observed-Adverse-Effect Level (LOAEL) for exposure to microbial bioaerosols in ambient air. Expertise of both exposure and outcome assessment should be brought together to enable standardization of experimental animal studies with properly generated aerosols aiming to derive health-based exposure limits.

Evaluation of exposure-response relationships for health effects of microbial bioaerosols - A systematic review.

Studies suggest adverse health effects following exposure to bioaerosols in the environment and in particular at workplaces. However, there is still a lack of health-related exposure limits based on toxicological or epidemiological studies from environmental health or from the working environment. The aim of this study was to derive health-based exposure limits for bioaerosols that can protect the general population as group "at risk" via environmental exposure using analysis of peer-reviewed studies related to occupational medicine, indoor air and environmental health. The derivation of exposure limits should be conducted by the members of a bioaerosol expert panel according to established toxicological criteria. A systematic review was performed in Medline (PubMed) including studies containing both data on exposure measurements and observed health outcomes. In addition, literature recommended by the experts was considered. A comprehensive search strategy was generated and resulted in a total of n=1569 studies in combination with the literature recommendations. Subsequently, abstracts were screened using defined exclusion criteria yielding a final number of n=44 studies. A standardized extraction sheet was used to combine data on health effects and exposure to different bioaerosols. After full-text screening and extraction according to the defined exclusion criteria n=20 studies were selected all related to occupational exposures comprising the working areas wood processing, farming, waste processing and others. These studies were analyzed in collaboration with the bioaerosol expert network in terms of suitability for derivation of health-related exposure limits. The bioaerosol expert network concluded that none of the analyzed studies provided suitable dose-response relationships for derivation of exposure limits. The main reasons were: (1) lack of studies with valid dose-response data; (2) diversity of employed measuring methods for microorganisms and bioaerosol-emitting facilities; (3) heterogeneity of health effects; (4) insufficient exposure assessment. However, several indicator parameters and exposure concentrations could be identified for different bioaerosol-emitting facilities. Nevertheless, health-related exposure limits are urgently needed especially in approval procedures of facilities like composting plants or livestock farms emitting bioaerosols in the neighbourhood of residents. In the regulatory toxicology framework, it is common to use animal experimental studies for derivation of general exposure limits if appropriate environmental epidemiological studies on harmful substances are lacking. This might be another possibility to obtain health-related exposure limits for specific bioaerosol parameters. Furthermore, we recommend to use suitable measurable outcome parameters related to bioaerosols; to measure bioaerosols according to a protocol representative for exposure pattern and duration at the particular work place; to develop standardized detection methods for indicator parameters; to combine different detection methods to compensate for the limitations of each method; to apply new analysis methods to identify the real risk potential.

Assessment of long-term health risks after accidental exposure using haemoglobin adducts of epichlorohydrin.

On September 9th, 2002, two goods trains collided in Bad Münder, Lower Saxony, causing the release of more than 40 metric tonnes of epichlorohydrin (1-chloro-2,3-epoxypropane) into the environment. A human biomonitoring study was performed to evaluate the accidental exposure to epichlorohydrin and to assess the possible long-term, i.e. carcinogenic health effects. This was done on the basis of a biochemical effect monitoring using the N-(3-chloro-2-hydroxypropyl)valine and the N-(2,3-dihydroxypropyl)valine haemoglobin adducts of epichlorohydrin in blood to respond to missing ambient monitoring immediately after the crash. N-(3-chloro-2-hydroxypropyl)valine adduct levels above the LOQ (25 pmol/g globin) ranged from 32.0 to 116.4 pmol/g globin in 6 out of 628 samples. The N-(2,3-dihydroxypropyl)valine adduct was not detected above the LOD (10 pmol/g globin) in any of the blood samples. Based on the quantified N-(3-chloro-2-hydroxypropyl)valine adduct values, the body doses after two days of exposure were estimated to be in the range of 1.7-6.2 nmol/kg body weight. The reverse estimation of the external exposure leads to cumulative additional lifetime cancer risks ranging from 2.61×10(-8) to 9.48×10(-8). The estimated excess lifetime cancer risks have to be assessed as extremely low. Our biomonitoring study facilitated the dialogue between individuals and groups concerned and authorities, because suspected or occurred exposures and risks to human health could be quantified and interpreted in a sound manner.