RESUMEN
In the process of registration of substances of Unknown or Variable Composition, Complex Reaction Products or Biological Materials (UVCBs), information sufficient to enable substance identification must be provided. Substance identification for UVCBs formed through petroleum refining is particularly challenging due to their chemical complexity, as well as variability in refining process conditions and composition of the feedstocks. This study aimed to characterize compositional variability of petroleum UVCBs both within and across product categories. We utilized ion mobility spectrometry (IMS)-MS as a technique to evaluate detailed chemical composition of independent production cycle-derived samples of 6 petroleum products from 3 manufacturing categories (heavy aromatic, hydrotreated light paraffinic, and hydrotreated heavy paraffinic). Atmospheric pressure photoionization and drift tube IMS-MS were used to identify structurally related compounds and quantified between- and within-product variability. In addition, we determined both individual molecules and hydrocarbon blocks that were most variable in samples from different production cycles. We found that detailed chemical compositional data on petroleum UVCBs obtained from IMS-MS can provide the information necessary for hazard and risk characterization in terms of quantifying the variability of the products in a manufacturing category, as well as in subsequent production cycles of the same product.
RESUMEN
The thyroid gland, and its associated endocrine hormones, is a growing area of interest in regulatory toxicology due to its important role in metabolism, growth and development. This report presents a review of the toxicology data on chemically complex petroleum streams for thyroid hormone effects. Toxicological summaries and studies from all available published and un-published sources were considered, drawing upon the European REACH regulatory submissions for 19 petroleum streams, with in depth review of 11 individual study reports and 31 published papers on related products or environmental settings. Findings relevant to thyroid pathology or thyroid hormone homeostasis were specifically sought, summarized, and discussed. A total of 349 studies of 28-days or longer duration were considered in the review, including data on mice, rats, rabbits, dogs, humans, and fish. The thyroid was almost invariably not a target organ in these studies. Three rodent studies did find thyroid effects; one on a jet fuel product (JP-8), and two studies on a heavy fuel oil product (F-179). The JP-8 product differs from other fuels due to the presence of additives, and the finding of reduced T4 levels in mice in the study occurred at a dose that is above that expected to occur in environmental settings (e.g. 2000mg/kg). The finding for F-179 involved thyroid inflammation at 10-55mg/kg that co-occurred with liver pathology in rats, indicating a possible secondary effect with questionable relevance to humans. In the few cases where findings did occur, the polycyclic aromatic hydrocarbon (PAH) content was higher than in related substances, and, in support of one possible adverse outcome pathway, one in-vitro study reported reduced thyroid peroxidase (TPO) activity with exposure to some PAH compounds (pyrene, benzo(k)fluoranthene, and benzo(e)pyrene). However, it could not be determined from the data available for this review, whether these specific PAH compounds were substantially higher in the JP-8 or F-179 products than in studies in which thyroid effects were not observed. Thus, a few products may carry a weak potential to affect the thyroid at high doses in rodents, possibly through secondary effects on the rodent liver or possibly through a pathway involving the inhibition of TPO by specific members of the PAH family. Human epidemiology evidence found weak and inconsistent effects on the thyroid but without identification of specific chemicals involved. Two studies in petroleum workers, which found a lower rate of morbidity and mortality overall, reported a statistically significant increase in thyroid cancer, but the small number of cases could not exclude confounding variables as possible explanations for the statistical findings. Overall, the available data indicates a low potential for thyroid hormone effects from exposure to petroleum streams, especially when the aromatic content is low. Because regulatory studies for most chemicals do not include detailed thyroid function or receptor studies, it remains possible that subclinical effects on this system may exist that were not detectable using conventional pathology or hormone measurements.
Asunto(s)
Disruptores Endocrinos/toxicidad , Contaminación por Petróleo/efectos adversos , Petróleo/toxicidad , Enfermedades de la Tiroides/inducido químicamente , Glándula Tiroides/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Humanos , Medición de Riesgo , Enfermedades de la Tiroides/epidemiología , Enfermedades de la Tiroides/metabolismo , Enfermedades de la Tiroides/fisiopatología , Glándula Tiroides/metabolismo , Glándula Tiroides/fisiopatología , Factores de Tiempo , Pruebas de ToxicidadRESUMEN
Comparative assessment of potential human health impacts is a critical step in evaluating both chemical alternatives and existing products on the market. Most alternatives assessments are conducted on a chemical-by-chemical basis and it is seldom acknowledged that humans are exposed to complex products, not individual substances. Indeed, substances of Unknown or Variable composition, Complex reaction products, and Biological materials (UVCBs) are ubiquitous in commerce yet they present a major challenge for registration and health assessments. Here, we present a comprehensive experimental and computational approach to categorize UVCBs according to global similarities in their bioactivity using a suite of in vitro models. We used petroleum substances, an important group of UVCBs which are grouped for regulatory approval and read-across primarily on physico-chemical properties and the manufacturing process, and only partially based on toxicity data, as a case study. We exposed induced pluripotent stem cell-derived cardiomyocytes and hepatocytes to DMSO-soluble extracts of 21 petroleum substances from five product groups. Concentration-response data from high-content imaging in cardiomyocytes and hepatocytes, as well as targeted high-throughput transcriptomic analysis of the hepatocytes, revealed distinct groups of petroleum substances. Data integration showed that bioactivity profiling affords clustering of petroleum substances in a manner similar to the manufacturing process-based categories. Moreover, we observed a high degree of correlation between bioactivity profiles and physico-chemical properties, as well as improved groupings when chemical and biological data were combined. Altogether, we demonstrate how novel in vitro screening approaches can be effectively utilized in combination with physico-chemical characteristics to group complex substances and enable read-across. This approach allows for rapid and scientifically-informed evaluation of health impacts of both existing substances and their chemical alternatives.
RESUMEN
This review of the toxicology of mineral spirits covers studies of the major classes of mineral spirits and several toxicologically important mineral spirit constituents. This review cites data from numerous previously unpublished animal toxicology studies conducted on mineral spirits during the past 30 years, expanding the existing database on the toxicology of this group of hydrocarbon solvents. The data can be used to better evaluate the potential effects associated with exposure to these materials, including health and environmental reviews such as the U.S. Environmental Protection Agency High Production Volume (HPV) chemical program and the Organization for Economic Cooperation and Development (OECD) HPV Screening Information Data Set (SIDS) program. The majority of animal toxicology studies in the available literature were conducted on mineral spirits categorized as ASTM D235 Type I Class A (149 degrees C to 213 degrees C boiling range; 8% to 22% aromatics) and demonstrate that Type I Class A mineral spirits have a low order of acute toxicity and do not produce significant systemic effects. Some additional studies conducted with ASTM D235 Type II Class C mineral spirits (177 degrees C to 213 degrees C boiling range; < 2% aromatics) suggest that Type II Class C mineral spirits have similar toxicity to Type I Class A mineral spirits, though there is some evidence that Type II, Class C mineral spirits have a lesser degree of central nervous system (CNS) effects than the higher aromatic containing Type I Class A materials. In addition, toxicity data on selected chemical constituents of mineral spirits (e.g., n-nonane, n-decane, n-undecane) indicate that these chemicals have similar toxicological properties to mineral spirits. Overall, the data showed that mineral spirits have a low order of acute toxicity and do not appear to produce toxicologically relevant systemic effects. Ongoing studies are evaluating the concerns associated with chronic low-level exposure and central nervous system effects.