Human Toxicity Data Research Articles

Using cephalopod-inspired chemistry to extend long-wavelength ultraviolet and visible light protection of mineral sunscreens.

The emergence of new human and environmental-related toxicity data associated with some common UV filters has catalysed growing interest in the inclusion of boosters and stabilizing ingredients in sunscreens. One approach is to incorporate alternative materials inspired by or mimetic of systems in biology, which offer a notable evolutionary advantage of multifunctionality and stability with increased biocompatibility. We describe the use of a natural product, Xanthochrome® (INCI: Ammonium Xanthommatin), in a series of studies designed to not only assess its safety with marine systems but also its formulation compatibility and function in water-in-oil mineral sunscreens. Xanthochrome is the synthetic form of the naturally occurring chromophore xanthommatin (XA) present in cephalopod skin, which doubles as a photostable antioxidant; however, it has never been explored in combination with mineral UV filters in finished formulations. Given the recent controversies associated with the environmental toxicological effects of some chemicals used in sunscreens, the safety of XA with coral cuttings was first validated at concentrations 5× above those used in our formulations. Next, a particle-based delivery of XA was designed and incorporated into a zinc oxide (ZnO)-based water-in-oil sunscreen, where the SPF, critical wavelength, and visible light (VL) blocking potential were measured. We observed no adverse effects of XA at 100 mg/L when tested with coral cuttings, demonstrating its safety at concentrations exceeding those used in our sunscreens. When formulated with ZnO-based sunscreens, the inclusion of XA increased the total UV absorbance profile by 28% and the total blocking potential of VL by 45%. The formulations also elicited no dermal irritation or sensitization in a human insult repeat patch test (N = 100 subjects). XA is differentiated as a photostable, water-soluble compound that is a VL booster proven safe for skin and coral cuttings. To the best of our knowledge, there are no other boosters that can be classified as such, despite a growing body of literature highlighting the need in the industry.

Microplastics in environment: a comprehension on sources, analytical detection, health concerns, and remediation.

Contamination of ecosystems by microplastics (MPs) has been reported intensively worldwide in the recent decade. A trend of reports indicated their presence in the atmosphere; food items and soil ecosystems are rising continuously. Literature evidenced that MPs are abundant in seawater, beach sand, drinking water, agricultural soils, wastewater treatment plant (WWTP) effluent, and the atmosphere. The greater abundance of MPs in the environment has led to their invasion of seafood, human-consumed food items such as table salts, beverages, takeout food containers, and disposable cups, marine biological lives, and creating serious health hazards in humans. Moreover, the absence of guidelines and specifications for controlling MPs in the environment makes the situation alarming, and the human toxicity data of MPs is scarce. Thereby, the toxicity assessment of MPs in humans is of greater concern. This review compiles the updated information on the potential sources of MPs in different components of the environment (viz.soil, water, and air), their analysis methods, effects on human health, and remediation methods.

The Effect of Experimental Protocol on the Toxicity of Saxitoxin in Mice.

Regulatory limits for toxins in shellfish are required to ensure the health of consumers. However, these limits also impact the profitability of shellfish industries making it critical that they are fit for purpose. Since human toxicity data is rarely available, the setting of regulatory limits is dependent on animal data which can then be extrapolated for use in the assessment of human risk. The dependence on animal data to keep humans safe means that it is critical that the toxicity data used is robust and of high quality. Worldwide, the protocols used in toxicity testing are varied, making it hard to compare results and adding confusion over which results better reflect the true toxicity. In this study, we look at the effect of mouse gender, i.p. dose volume, mouse body weight and feeding protocols (both acute and sub-acute) on the toxicity of saxitoxin. This allowed the effect of different variables used in toxicity testing to be understood and showed that the feeding protocol used in both acute and sub-acute studies greatly influenced the toxicity of saxitoxin in mice. Therefore, the adoption of a standard protocol for the testing of shellfish toxins is recommended.

Towards FAIR nanosafety data.

Nanotechnology is a key enabling technology with billions of euros in global investment from public funding, which include large collaborative projects that have investigated environmental and health safety aspects of nanomaterials, but the reuse of accumulated data is clearly lagging behind. Here we summarize challenges and provide recommendations for the efficient reuse of nanosafety data, in line with the recently established FAIR (findable, accessible, interoperable and reusable) guiding principles. We describe the FAIR-aligned Nanosafety Data Interface, with an aggregated findability, accessibility and interoperability across physicochemical, bio-nano interaction, human toxicity, omics, ecotoxicological and exposure data. Overall, we illustrate a much-needed path towards standards for the optimized use of existing data, which avoids duplication of efforts, and provides a multitude of options to promote safe and sustainable nanotechnology.

Oncofertility Information Available for Recently Approved Novel Non Cytotoxic and Immunotherapy Oncology Drugs.

We reviewed the available animal and human reproductive function studies of recently approved noncytotoxic oncology drugs. We reviewed the oncofertility information in the prescribing information for the US Food and Drug Administration (FDA)-approved products and/or the product information and consumer medicine information for Therapeutic Goods Administration (TGA)-approved drugs of 32 novel oncology drugs approved between 2014 and 2018 in the United States and/or Australia supplemented by a literature review for additional reproductive effects. No human studies were available on the reproductive effects of all 32 drugs. A systematic literature review of animal reproductive toxicity studies provided only very limited data with nine drugs displaying impaired male fertility, three impaired female fertility, and nine producing impaired fertility in both male and female animals. Two drugs in the study are reported to have no demonstrable impact on fertility in animal reproductive toxicity studies and nine are reported to have unknown effects on fertility. Of the 32 newly listed drugs, only 4 had recommendations regarding potential human fertility risks and accordingly advised clinicians about fertility preservation procedures for patients. The lack of human data and limited animal reproductive toxicity data raises concerns about the potential impact of these novel oncology drugs on human fertility and reproductive function. Consequently, adequate oncofertility recommendations, including for fertility preservation procedures, counselling for psychological or cost implications, and future prognosis for fertility are hindered by this paucity of relevant data. More data on human reproductive effects of novel oncology drugs is urgently required to facilitate effective use of the growing array of oncofertility care options available.

A systematic approach for prioritizing landfill pollutants based on toxicity: Applications and opportunities

Landfills in the United States are a significant source of pollution to ground and surface water. Current environmental regulations require detection and/or monitoring assessments of landfill leachate for contaminants that have been deemed particularly harmful. However, the lists of contaminants to be monitored are not comprehensive. Further, landfill leachate composition varies over space and time, and thus the contaminants, and their corresponding toxicity, are not consistent across or within landfills. One of the main objectives of this study was to prioritize contaminants found in landfill leachate using a systematic, toxicity-based prioritization scheme. A literature review was conducted, and from it, 484 landfill leachate contaminants with available CAS numbers were identified. In vitro, in vivo, and predicted human toxicity data were collected from ToxCast, ECOTOX, and CTV Predictor, respectively. These data were integrated using the Toxicological Priority Index (ToxPi) for the 322 contaminants which had available toxicity data from at least two of the databases. Four modifications to this general prioritization scheme were developed to demonstrate the flexibility of this scheme for addressing varied research and applied objectives. The general scheme served as a basis for comparison of the results from the modified schemes, and allowed for identification of contaminants uniquely prioritized in each of the schemes. The schemes outlined here can be used to identify the most harmful contaminants in environmental media in order to design the most relevant mitigation strategies and monitoring plans. Finally, future research directions involving the combination of these prioritization schemes and non-target global metabolomic profiling are discussed.

4,5,6,7-Tetrabromo-2,3-dihydro-1,1,3-trimethyl-3-(2,3,4,5-tetrabromophenyl)-1H-indene (OBTMPI): Levels in humans and in silico toxicological profiles.

Limited human exposure and toxicity data are currently available for 4,5,6,7-Tetrabromo-2,3-dihydro-1,1,3-trimethyl-3-(2,3,4,5-tetrabromophenyl)-1H-indene (OBTMPI), a flame retardant often used for high temperature application of various polymer materials. Levels of OBTMPI in a cohort population that includes children and their co-residing parents (n=217) in Canada were determined. Detection frequency of OBTMPI in the samples was 22.6%. OBTMPI levels were in general at sub-to low ng/g lipid weight level with a 95th percentile at 15.6ng/g lipid weight. Compared to an earlier study conducted in 2008-2009 in the same region, results from this study show an increase in both detection frequency and concentration of OBTMPI. In silico toxicity predictions using Multicase CaseUltra and Leadscope Model Applier suggested that OBTMPI, and its possible metabolites in humans, while unlikely to be carcinogenic or mutagenic, exhibit some estrogen antagonist, androgen antagonist and estrogen binding capability reflective of possible endocrine disrupting properties.

Neonicotinoid Poisoning Presenting As Methemoglobinemia – An Unusual Presentation

Neonicotinoids are considered a class of insecticides that are less toxic to human beings than organophosphates, carbamates, pyrethroids and organochlorides. Neonicotinoids are developed and launched in the market in the absence of direct human toxicity data. Human toxicity is extrapolated from animal studies, whose relevance is unclear.Despite its widespread use, very few cases have been reported. We report an unusual case of thiamethoxam poisoning-a 2nd generation neonicotinoid insecticide presenting as methemoglobinemia.

Soy Intake and Possible Adverse Health Effects in Nordic Children and Pregnant Women (Unborn Children)

Aim: To explore possible adverse health effects of high soy intake among children and pregnant women (unborn children) in the Nordic countries. Methods: A dietary exposure scenario with a high soy ...

Concise Review of Nickel Human Health Toxicology and Ecotoxicology

Nickel (Ni) metal and Ni compounds are widely used in applications like stainless steel, alloys, and batteries. Nickel is a naturally occurring element in water, soil, air, and living organisms, and is essential to microorganisms and plants. Thus, human and environmental nickel exposures are ubiquitous. Production and use of nickel and its compounds can, however, result in additional exposures to humans and the environment. Notable human health toxicity effects identified from human and/or animal studies include respiratory cancer, non-cancer toxicity effects following inhalation, dermatitis, and reproductive effects. These effects have thresholds, with indirect genotoxic and epigenetic events underlying the threshold mode of action for nickel carcinogenicity. Differences in human toxicity potencies/potentials of different nickel chemical forms are correlated with the bioavailability of the Ni2+ ion at target sites. Likewise, Ni2+ has been demonstrated to be the toxic chemical species in the environment, and models have been developed that account for the influence of abiotic factors on the bioavailability and toxicity of Ni2+ in different habitats. Emerging issues regarding the toxicity of nickel nanoforms and metal mixtures are briefly discussed. This review is unique in its covering of both human and environmental nickel toxicity data.

A robust Bayesian meta-analytic approach to incorporate animal data into phase I oncology trials.

Before a first-in-man trial is conducted, preclinical studies are performed in animals to help characterise the safety profile of the new medicine. We propose a robust Bayesian hierarchical model to synthesise animal and human toxicity data, using scaling factors to translate doses administered to different animal species onto an equivalent human scale. After scaling doses, the parameters of dose-toxicity models intrinsic to different animal species can be interpreted on a common scale. A prior distribution is specified for each translation factor to capture uncertainty about differences between toxicity of the drug in animals and humans. Information from animals can then be leveraged to learn about the relationship between dose and risk of toxicity in a new phase I trial in humans. The model allows human dose-toxicity parameters to be exchangeable with the study-specific parameters of animal species studied so far or non-exchangeable with any of them. This leads to robust inferences, enabling the model to give greatest weight to the animal data with parameters most consistent with human parameters or discount all animal data in the case of non-exchangeability. The proposed model is illustrated using a case study and simulations. Numerical results suggest that our proposal improves the precision of estimates of the toxicity rates when animal and human data are consistent, while it discounts animal data in cases of inconsistency.

The composition of nonbeverage alcohols consumed in Russia in 2015–2017

Introduction From previous research it is known that nonbeverage alcohols (NAs) were consumed by significant proportions of Russian population for drinking (e.g. 7% of working age males). In illegal NAs spirits other than ethanol may be used for their manufacturing. Such cases of illegal production from time to time manifest in outbreaks of deadly alcohol poisonings. The most recent such outbreak occurred in December 17–26 2016 in the Siberian city of Irkutsk, where 123 people, who drunk spirituous bath additive “Hawthorn” containing admixture of methanol, were poisoned, of whom 76 died. In a previous study conducted in 2005 NAs typically contained rectified highly concentrated ethanol. However, the study was conducted more than a decade ago and on a relatively small number of samples purchased only in one region of Russian Federation. To provide most up to date information on the problem we conducted a study of composition of NAs, which were available in retail in cities across the vast geography of Russia. Methods For analysis of composition we selected 92 samples of NAs, which were purchased in a survey of NAs availability in 50 Russian cities between 2015 and 2017. Consumption for drinking of selected types of NAs has been confirmed in simultaneous survey of subjects with substance use disorders recruited in narcology clinic in Kazan, Russia in 2015–2017. Gas chromatography and mass spectrometry (GC-MS) on a Hewlett-Packard 7820A gas chromatograph were used to determine NAs composition. For detection of extractable organic components we employed a method of micro extraction in a vial. For this purpose nonbeverage alcohol, internal standard and extragent were aliquoted to a standard vial for auto injector. After extraction of organic compounds inside the vial in a vibro shaker and separation of organic layer the later was taken for GC-MS analysis. The literature on toxicity of identified admixtures was reviewed. Results The majority of NAs contained 60 v/v% or more ethanol and represented either pure solutions of ethanol without other admixtures, or contained specific active ingredients. The following substances were identified in significant amounts in some of the analysed samples: –eau-de-colognes and some lotions consumed for drinking (e.g. Troynoi, Shipr, Ogurechniy, Hawthorn): propylene glycol and polypropylene glycols (e.g. dypropylene glycol), phenylethyl alcohol, linalyl anthranilate, ethyl salicylate, diphenyl ether; butylated hydroxytoluene, 3-phenyl-2-butanol, benzenemethanol, cyclamal, lilyal, and other substances; –cosmetic lotions: diethyl phthalate; –antiseptics: formic acid; –medicinal tinctures: compounds of plant extracts. Some medicinal tinctures sold in 100 ml bottles and cosmetic lotions didn’t contain active substances (e.g. capsaicin, flavouring agents, plant extracts). Conclusions On some identified compounds (e.g. 3,3′-oxybis-2-butanol; lilyal, etc.) limited or no human toxicity data is available, especially when ingested. Propylene glycols, although classed as substances with low toxicity, when ingested in large amounts may cause metabolic acidosis, cardiac arrhythmias and even cardiac arrest. Antiseptic containing 1.4% solution of formic acid in 70% ethanol when swallowed may cause multiple toxic effects of various severities, depending on amount consumed. These include gastrointestinal mucous burns, ulcerations, and bleeding; circulatory collapse, renal failure, ischemic lesions in liver and heart; late oesophageal, gastric and pyloric stenosis; asphyxial death due to glottic oedema, or due to toxic shock among others. Absence of active substances in some NAs suggests their illegal nature. Control of NAs production and consumption in Russia must be a priority as toxicity of some of them is determined not only by cheap concentrated ethanol, but also by other toxic admixtures. More toxicological research is needed on interaction of various compounds of NAs with ethanol and its metabolites.

Hexavalent Chromium in Drinking Water

The risk assessment of chromium in drinking water is complex. To better understand this complexity, the essential information on exposure, analytical and treatment methods, toxicology, and mode of action (MOA) on which agencies based their risk assessments are provided. Humans are exposed to an average of 0.2–2 μg hexavalent chromium per liter in drinking water through natural erosion of soil and rocks or by contamination from industrial sources. Internationally, drinking water limits for total chromium range from 50 to 100 μg/L. These values are based on intestinal toxicity data from experimental animals, since human toxicity data via the oral route are lacking. MOA analysis supports a progression from noncancer to cancer effects via a nonmutagenic MOA and therefore a threshold approach is appropriate for the risk assessment of chromium in drinking water. Drinking water limits derived from this approach are measureable by available analytical methods and achievable by available treatment technologies, and are protective of both cancer and noncancer effects.

Moderate doses of commercial preparations of Ginkgo biloba do not alter markers of liver function but moderate alcohol intake does: A new approach to identify and quantify biomarkers of ‘adverse effects’ of dietary supplements

It is difficult to determine if certain dietary supplements are safe for human consumption. Extracts of leaves of Ginkgo biloba trees are dietary supplements used for various purported therapeutic benefits. However, recent studies reported they increased risk of liver cancer in rodents. Therefore, this study assessed the association between ginkgo consumption and liver function using NHANES 2001–2012 data (N = 29,684). Since alcohol is known to adversely affect liver function, association of its consumption with liver function was also assessed. Alcohol and ginkgo extract intake of adult consumers and clinical markers of liver function (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, bilirubin) were examined. Moderate consumers of alcohol (0.80 ± 0.02 drinks/day) had higher levels of aspartate aminotransferase and gamma glutamyl transferase than non-consumers (P < 0.001). There was no difference (P > 0.01) in levels of markers of liver function in 616 ginkgo consumers (65.1 ± 4.4 mg/day intake) compared to non-consumers. While moderate alcohol consumption was associated with changes in markers of liver function, ginkgo intake as typically consumed by U.S. adults was not associated with these markers. Biomarkers measured by NHANES may be useful to examine potential adverse effects of dietary supplements for which insufficient human adverse event and toxicity data are available. Trial registration numberNot applicable, as this is secondary analysis of publicly released observational data (NHANES 2001–2012).

Boron exposure through drinking water during pregnancy and birth size

BackgroundBoron is a metalloid found at highly varying concentrations in soil and water. Experimental data indicate that boron is a developmental toxicant, but the few human toxicity data available concern mostly male reproduction. ObjectivesTo evaluate potential effects of boron exposure through drinking water on pregnancy outcomes. MethodsIn a mother-child cohort in northern Argentina (n=194), 1–3 samples of serum, whole blood and urine were collected per woman during pregnancy and analyzed for boron and other elements to which exposure occurred, using inductively coupled plasma mass spectrometry. Infant weight, length and head circumference were measured at birth. ResultsDrinking water boron ranged 377–10,929μg/L. The serum boron concentrations during pregnancy ranged 0.73–605μg/L (median 133μg/L) and correlated strongly with whole-blood and urinary boron, and, to a lesser extent, with water boron. In multivariable-adjusted linear spline regression analysis (non-linear association), we found that serum boron concentrations above 80μg/L were inversely associated with birth length (B−0.69cm, 95% CI −1.4; −0.024, p=0.043, per 100μg/L increase in serum boron). The impact of boron appeared stronger when we restricted the exposure to the third trimester, when the serum boron concentrations were the highest (0.73–447μg/L). An increase in serum boron of 100μg/L in the third trimester corresponded to 0.9cm shorter and 120g lighter newborns (p=0.001 and 0.021, respectively). ConclusionsConsidering that elevated boron concentrations in drinking water are common in many areas of the world, although more screening is warranted, our novel findings warrant additional research on early-life exposure in other populations.

Derivation of an occupational exposure limit for an inhalation analgesic methoxyflurane (Penthrox®)

Methoxyflurane (MOF) a haloether, is an inhalation analgesic agent for emergency relief of pain by self administration in conscious patients with trauma and associated pain. It is administered under supervision of personnel trained in its use. As a consequence of supervised use, intermittent occupational exposure can occur. An occupational exposure limit has not been established for methoxyflurane. Human clinical and toxicity data have been reviewed and used to derive an occupational exposure limit (referred to as a maximum exposure level, MEL) according to modern principles. The data set for methoxyflurane is complex given its historical use as anaesthetic. Distinguishing clinical investigations of adverse health effects following high and prolonged exposure during anaesthesia to assess relatively low and intermittent exposure during occupational exposure requires an evidence based approach to the toxicity assessment and determination of a critical effect and point of departure. The principal target organs are the kidney and the central nervous system and there have been rare reports of hepatotoxicity, too. Methoxyflurane is not genotoxic based on in vitro bacterial mutation and in vivo micronucleus tests and it is not classifiable (IARC) as a carcinogenic hazard to humans. The critical effect chosen for development of a MEL is kidney toxicity. The point of departure (POD) was derived from the concentration response relationship for kidney toxicity using the benchmark dose method. A MEL of 15 ppm (expressed as an 8 h time weighted average (TWA)) was derived. The derived MEL is at least 50 times higher than the mean observed TWA (0.23 ppm) for ambulance workers and medical staff involved in supervising use of Penthrox. In typical treatment environments (ambulances and treatment rooms) that meet ventilation requirements the derived MEL is at least 10 times higher than the modelled TWA (1.5 ppm or less) and the estimated short term peak concentrations are within the MEL. The odour threshold for MOF of 0.13–0.19 ppm indicates that the odour is detectable well below the MEL. Given the above considerations the proposed MEL is health protective.

Unknown levels, uncertain sources: or all we know regarding Humans and Organotin compounds

Human activities are responsible for the production and transformation of thousands of chemical compounds. These chemicals will at some point be released into the environment, being therefore potentially available to be accumulated by wildlife and humans. Organotins (OTs) are among such chemicals. With an annual production of over 60,000 tons, they comprise a vast number of compounds used with three main purposes: as biocides; as stabilizers in the plastics industry; and as catalysts for the production of polyurethane foams and silicones. The excellent biocidal properties of tributyltin (TBT) (and its effects on non-target species), are most probably the cause for OTs notoriety. This compound was extensively used in antifouling paints which lead to a global contamination of the marine environment. Due to its persistency and demonstrated deleterious effects, including, e.g., endocrine disruption, TBT was banned on a global scale in 2008. Despite the tremendous attention from the scientific community to the levels and effects of OTs in the aquatic environment the same level of effort was not undertaken regarding humans. However, the widespread industrial application grants OTs a ubiquitous presence in every aspect of human life through clothes, pillows, toys, wallpaper, plastic food containers, pipes (including drinking water mains and household piping) and medical devices. This scenario creates frequent exposure opportunities by dermal contact with consumer products or through ingestion of contaminated dust, which are cumulative with the ingestion of contaminated food (particularly seafood). Without surprise, organotins have already been detected in human samples and toxicity data reveals that they are endocrine disruptors, imunotoxicants, and carcinogens, being recently linked to obesity. In this wok a thorough review on the OTs burden in human tissues is performed. Possible exposure sources are also unraveled and risk towards humans addressed.

Health related guide values for drinking-water since 1993 as guidance to assess presence of new analytes in drinking-water

Regulatory toxicologists, when going into assessment of a new analyte in drinking-water, very often miss the occasion to revert to scientifically consensual virtually safe lifetime exposure reference doses and corresponding health-related guide values (HRGV) for drinking-water, be those derived either to avoid concern over "threshold effects" or concern over exceedance of an unacceptable non-threshold cancer risk level. They then need a more restrictive precautionary yet science-compatible approach to directly avoid concern over the presence (measured concentration) of a new analyte in drinking-water. Therefore, the German Environment Agency (UBA, Umweltbundesamt) decided in 2003 to extrapolate international toxicological expertise collected since 1993 from assessing "old" analytes in drinking-water on new ones in form of five HRIV=health related indication values. They indicate the reasonable lowest maximal concentration from which on tiered or stepwise human toxicological evaluation of a new analyte might be necessary and meaningful. Their regulatory-toxicological function is that of placeholders as long as a possibly higher scientific HRGV or a surrogate value based on a threshold of toxicological concern (TTC) was not broadly agreed by science. The five-step HRIV scale between 0.01 and 3.0 μg/l combines international toxicological experience gained from "old" analytes since 1993 with the concepts of safety factors (SF(D)) to assess database deficiency and science-related extrapolation factors (EF) to extrapolate experimental data on humans. Each HRIV is valid and safe for a 2 l/day drinking-water exposure scenario either counting for 10% relative source contribution (compounds with threshold effects) or for a lifetime non-threshold cancer risk of up to 10(-6) and is the higher the more positive information exists regarding possible effects at critical toxic endpoints and for length of possible exposure. Past (historical) and present evaluations of "old" analytes were available in form of hundreds of HRGVs to count in 2 liters per day and person for 10% RSC or a 10(-6) non-threshold risk. These HRGVs were calculated by the present author either from ADI-, TDI- or RfD-values derived since 1993 by six large health authorities or they were identified directly at their websites or in the literature, always looking for confirmed or assumed worldwide relevance for drinking-water (resources). 36 of these up to 200 "old" analytes were ascribed since 1993 at least once an HRGV at or below 1 μg/l for (confirmed or provisionally assumed) "high" or "very high" threshold chronic toxicity. None but one of the corresponding 113 scientific HRGVs fell distinctly short of 0.3 μg/l. Only 14 carcinogens turned out as being relevant for drinking-water due to confirmed occurrence and coincident toxicological significance there. 13 of these exhibited a structural alert for genotoxicity. Ten of these 13 were "high-potency" genotoxic carcinogens with presently calculated non-threshold 10(-6) risk minimal HRGVs between 0.06 μg/l and 0.005 μg/l (9 compounds) or possibly down to 0.0007 μg/l (1 compound). This motivated UBA to propose a precautionary range between a minimal HRIV0=0.01 and a HRIV1=0.1 μg/l to assess new analytes bearing a structural alert for genotoxicity. The HRGVs for the remaining three (from 13) carcinogens with alerts for genotoxicity were at best similar for both genotoxic and non-genotoxic effects and higher or equal to 0.3 μg/l. Therefore, a minimal HRIV of 0.01 μg/l (HRIV0) or even 0.1 μg/l (HRIV1) would have appeared too low for assessing the presence in drinking-water of new analytes with no other human toxicity data than proven absence of both genotoxicity and of structural alerts for such. Instead, UBA proposes to provisionally assess such compounds by its next higher precautionary of HRIV3=0.3 μg/l. Any value once set is open for falsification upwards to either 1.0 μg/l (HRIV4) or 3.0 μg/l (HRIV5) or even for being replaced by an HRGV>3.0 μg/l if pertinent high toxicity effect potentials different from genotoxicity are similarly ruled out by either mechanistic and TTC-based arguments or a tiered experimental (in vitro and/or in vivo) approach. Regulatory-toxicological expertise gained since 1993 with "old" analytes in drinking-water (resources) and its extrapolation by analogy on new analytes with patchy human toxicological database allows for provisional assessment of their presence in drinking-water in form of five precautionary HRIVs. Selecting a HRIV, instead referring to a TTC or a virtually safe reference dose, just asks an expert judgment on the degree of formal completeness and informational potential of a new analyte's human toxicity database. Exceedance of a HRIV indicates need for supplementary toxicological data to improve assessment, their nature and comprehensiveness depending on degree and expected length of exceedance. The regulatory function of a HRIV is that of a placeholder for a possibly higher TTC-based surrogate HRGVTTC or a highest possible science-based HRGV.

Human Environmental and Occupational Exposures to Boric Acid: Reconciliation with Experimental Reproductive Toxicity Data

The reproductive toxicity of boric acid and borates is a matter of current regulatory concern. Based on experimental studies in rats, no-observed-adverse-effect levels (NOAELs) were found to be 17.5 mg boron (B)/kg body weight (b.w.) for male fertility and 9.6 mg B/kg b.w. for developmental toxicity. Recently, occupational human field studies in highly exposed cohorts were reported from China and Turkey, with both studies showing negative results regarding male reproduction. A comparison of the conditions of these studies with the experimental NOAEL conditions are based on reported B blood levels, which is clearly superior to a scaling according to estimated B exposures. A comparison of estimated daily B exposure levels and measured B blood levels confirms the preference of biomonitoring data for a comparison of human field studies. In general, it appears that high environmental exposures to B are lower than possible high occupational exposures. The comparison reveals no contradiction between human and experimental reproductive toxicity data. It clearly appears that human B exposures, even in the highest exposed cohorts, are too low to reach the blood (and target tissue) concentrations that would be required to exert adverse effects on reproductive functions.

Genotoxic potential of arsenic at its reference dose

Arsenic, a highly hazardous contaminant in our drinking water, accounts for various toxic effects (including cancer) in human. However, intake of arsenic @0.3μgkg−1day−1 through drinking water, containing arsenic at its guideline value or maximum contaminant limit (10μgL−1), has been estimated to pose very little or no measurable risk to cancer in humans. The value also appears to be equal to the human reference dose (or index dose) of arsenic based on human skin toxicity data. The present work was a quantitative assessment of the genotoxic potential of arsenic in mice at doses equivalent to its human reference dose as well as its multiples. Significant increases in the frequencies of chromosome abnormalities in the bone marrow cells were registered over the control level upon exposure to all the doses of arsenic including its reference dose (or index dose). The assessment of arsenic genotoxicity in humans at low doses will therefore be highly instrumental in establishing a permissible limit of arsenic in drinking water.