File Name: toxicological effects of perfluoroalkyl and polyfluoroalkyl substances .zip
- Toxicological and Health Effects of Per- and Polyfluoroalklyl Substance (PFAS) Mixtures
- Toxicological Effects of Perfluoroalkyl and Polyfluoroalkyl Substances
Toxicological and Health Effects of Per- and Polyfluoroalklyl Substance (PFAS) Mixtures
Ian T. E-mail: ian. Grouping strategies are needed for per- and polyfluoroalkyl substances PFAS , in part, because it would be time and resource intensive to test and evaluate the more than PFAS on the global market on a chemical-by-chemical basis. In this paper we review various grouping strategies that could be used to inform actions on these chemicals and outline the motivations, advantages and disadvantages for each.
Grouping strategies are subdivided into 1 those based on the intrinsic properties of the PFAS e. The least precautionary grouping approach reviewed advocates only grouping PFAS for risk assessment that have the same toxicological effects, modes and mechanisms of action, and elimination kinetics, which would need to be well documented across different PFAS. It is recognised that, given jurisdictional differences in chemical assessment philosophies and methodologies, no one strategy will be generally acceptable.
The guiding question we apply to the reviewed grouping strategies is: grouping for what purpose? The motivation behind the grouping e. This assessment provides the necessary context for grouping strategies such that they can be adopted as they are, or built on further, to protect human and environmental health from potential PFAS-related effects.
Structurally diverse PFAS are used in a wide variety of commercial products and industrial applications. For the majority of PFAS, little or no data on uses, properties and effects are available to determine how these chemicals may impact the health of living organisms.
But researching individual chemicals is both expensive and time consuming. It can take many years to gather the evidence needed under regulatory regimes to restrict harmful chemicals. It is becoming increasingly apparent that to effectively protect the public and environment from the wide range of possible PFAS-related environmental and human health effects, strategies should be sought to group PFAS for action, e.
Between and , 9 after about 50 years of continuous manufacture, 3M phased out all PFAS products derived from perfluorooctane sulfonyl fluoride POSF; C-8 and its C-6 and C homologues, which represented the first large-scale grouping of hundreds of PFAS for voluntary phase-out. Given the number of substitutions of long-chain PFAAs with other PFAS that are now also considered to be problematic, there is a need for more effective grouping strategies for the regulation of PFAS than the current approach of regulating only long-chain PFAAs and related substances.
In the Madrid Statement, 16 more than scientists and regulators suggested that PFAS should be managed as a class, and that production and use should be limited. This grouping of all PFAS for phase-out is based on concerns regarding the high persistence of PFAS, the lack of knowledge on chemical structures, properties, uses, and toxicological profiles of most PFAS currently in use, and the need for informed substitutions of problematic PFAS chemistries.
Innovation, in conjunction with regulation and economic incentives for the development of new technologies, should in time provide functional alternatives to even current essential uses of PFAS. The aims of this paper are to discuss 1 current and potential grouping strategies that inform PFAS assessment for various control actions, with advantages and disadvantages for each, 2 highlight motivations for action that could guide use of specific grouping approaches and 3 outline the way forward and remaining challenges in advancing these grouping approaches.
Most existing grouping approaches have been developed to protect human and environmental health from potential adverse effects resulting from exposure to the multiple PFAS in commerce.
Moreover, further motivations for grouping of PFAS are based on their environmental and biological persistence, the high number of individual PFAS, and the lessons learned from recent industrial substitution strategies. Proactive strategies concerning new or continued use of PFAS may benefit from more precautionary grouping approaches because these decisions will directly impact future exposures and because their implementation — at least avoidance of non-essential uses — will always be less costly than retrospective risk assessment and remediation.
On the other hand, decisions for how to group already emitted PFAS for the establishment of drinking water guidelines or environmental cleanup levels will have profound impacts on enforcement including costs and resource needs. It may therefore be necessary, in resource-constrained settings, to more strictly prioritize cleanup levels on the basis of established toxicological risk. The approaches that inform risk assessment, on the other hand, consider anticipated exposure when determining whether or not an adverse effect to human health or the environment may occur.
For example, the point of departure for establishing acceptable risk could be the no observed adverse effect level NOAEL for a critical toxicological endpoint. Risk assessment has typically been performed on a chemical-by-chemical basis, but there is some current focus on developing methods for combined risk assessment through estimation of cumulative exposure e.
Each individual approach is discussed in more detail in the following sections. It is important to note that the individual grouping approaches were developed for different purposes, have different data needs, and therefore cannot always be directly compared to each other. The selection of the grouping approach needs to account for the specific protection goal, data requirements and enforcement techniques. An advantage of this approach is that it is easily implementable to all PFAS for non-experts, i.
There are already a number of PFAS that are suggested to be bioaccumulative according to observations from bioaccumulation experiments. Indications of bioaccumulation that need further evaluation are the observations of a number of emerging and novel PFAS in top predators including humans. For example, perfluoroethylcyclohexane sulfonate has been detected in top predator fish in the Great Lakes 36 and in crucian carp in China. Both computational and empirical methods have been explored to estimate protein binding affinity.
In vitro methods include, among others, equilibrium dialysis 40 and fluorescence displacement. Computational methods are based on structure—property relationships and could potentially be used to estimate the bioaccumulation potential of novel and emerging PFAS.
For example, the protein affinity of certain legacy and novel PFAS was recently estimated using molecular dynamic approaches, 44 and protein affinity is a key determinant of bioaccumulation potential. Such structure—property relationships may also aid in estimating the elimination half-lives of PFAS, which is another important factor in determining bioaccumulation potential. Predictive approaches for bioaccumulation potential will be especially important for informing grouping, as they are proactive and resource-efficient in comparison to biomonitoring and laboratory testing in vitro or in vivo testing.
Short-chain PFAAs have not been reported to bioaccumulate in animals, 11 but are known to bioaccumulate in above-ground plant tissues shoots, leaves and fruit. A fundamental limitation of grouping according to bioaccumulation potential B is that for highly persistent chemicals, B may become less relevant if a high exposure is achieved via other pathways than uptake and accumulation within the body.
It has been argued 50 that B is not a sufficient criterion for protecting against poorly reversible effects because the residence time of highly persistent chemicals in the environment is often much greater than their residence time in humans and biota, which means that levels in organisms will be poorly reversible regardless of the magnitude of B. Hydrophobic substances with a high octanol—water partition coefficient K OW e.
Integration of the PLC criteria into a risk management framework may differ from country to country according to individual regulatory mandate. Specifically: i some fluoropolymers e. PFOA , which are widely distributed in the Asian environment 54 and can undergo long-range global transport, 55,56 ii there are concerns among scientists and regulators regarding the substitute processing aids used e.
HFPO-DA is now an SVHC under the EU REACH regulation , 15 iii a wide range of potentially hazardous byproducts have been observed in the environment near fluoropolymer manufacturing sites, 14,57,58 iv environmental emissions of these persistent polymers during use and at end of life are problematic given the current concern regarding persistent microplastics in the environment even if fluoropolymer plastic waste is of relatively low volume , 59 and v the best available technology for treatment of solid wastes is currently incineration, from which emissions of harmful chemicals including certain PFAS could occur if incineration is not operated according to international guidelines.
Although the arrowhead approach is an efficient way of assessing and regulating large groups of chemicals simultaneously there are some limitations. One limitation is that the approach may overlook the risks from the parent PFAS themselves, or intermediate degradation products that are formed along the pathway to the presumed arrowhead degradation products. For example, a recent study demonstrated that fluorotelomer alcohol FTOH is significantly more toxic to rodents than perfluorohexanoic acid PFHxA.
Challenges with the above groups are the lack of an exhaustive list of present precursors and analytical methods for individually measuring all relevant precursors to a specific PFAA in a certain medium.
Although it was primarily developed as a research tool, 70 the total oxidizable precursor TOP assay is a potential solution to quantifying PFAAs and their precursors. The TOP assay has been primarily applied to quantify precursors that can be oxidized to PFAAs in water samples, 70 although it has further been developed and applied to a wider range of sample types, e. Application of the TOP assay usually involves quantifying PFAAs in samples using targeted analysis before and after treatment with powerful oxidizing agents.
Levels of PFAAs in drinking water samples could be compared to drinking water guidelines after the samples have been treated with the TOP assay. An advantage of this approach is that precursors would be included that could be transformed in the water or metabolized to PFAAs inside the body after intake.
On the other hand, the TOP assay may not simulate environmental transformation and metabolic processes accurately. The assay is an aggressive oxidation process that generates shorter-chain PFAAs than natural environmental oxidation processes, and even degrades polyfluoroalkyl ether acids with —O—CFH— moieties.
Finally, the TOP assay has not to date been standardized so results from different laboratories may be inconsistent. TF comprises the sum of all fluorine as a surrogate for all inorganic and organic fluorinated substances in a sample. PIGE spectroscopy is an ion beam technique used for the analysis of fluorine in solid materials, and liquids after solid-phase extraction.
Today, TF is used in Denmark with an official indicator value of 0. Furthermore, it can inform if PFAS levels are increasing over time. If the indicator level is exceeded, this can justify further analyses needed for risk assessment. The fast application of TF methods and relatively simple evaluation of results yes and no for presence of fluorine is appealing. Assuming a 10 mg sample size, detection limits for TF were recently reported as 0. Depending on the sample type, a certain fraction of the TF can be extracted using organic solvents extractable organic fluorine, EOF.
If the unknown fraction of organofluorine substances is large in a given sample, then this can be probed using non-targeted analytical methods. They are therefore good screening approaches that can be followed up with non- or suspect-targeted analytical methods to identify substances in the unknown PFAS fraction. This approach may be considered precautionary and protective, but on the other hand, humans are exposed to a lot of unknown PFAS with unknown risks, which may be more toxic than the currently known ones.
Another disadvantage of this approach in its application to PFAS is that it will likely capture organofluorine substances that are currently not considered as PFAS e.
Efforts are underway to assess, further develop and standardize methods as well as to conduct inter-laboratory comparison studies. The simple additive toxicity approach has the advantage that it is easy to understand and environmental or health-based guidelines can be evaluated with current analytical methods. Furthermore, it is thought to be protective for humans and the environment in that the additive toxicity is based on the most toxic PFAS in the group.
Scientific shortcomings of the simple additive toxicity approach that sums multiple PFAS are that 1 it assumes an external dose-additive model 88,89 whereas elimination kinetics vary largely among individual PFAS, 90 2 the identified critical adverse effects, as well as modes and mechanisms of action, may vary for individual PFAS, 7 3 mixture toxicity may not be simply additive even if the critical adverse effects are the same 88,89 and 4 although multiple PFAS are included in these drinking water standards, many more PFAS are neglected.
Some possible solutions to the highlighted issues are discussed in the remaining approaches reviewed, below. Gomis et al. This suggests that relative external potency is in fact largely a measure of accumulation potential, and that it may be possible to set a single internal dose for a particular endpoint and sum across all PFAS. Further confirmation is needed that this observation holds across a wider variety of PFAS structures, as Gomis et al.
Moreover, the application of simple addition of effective internal dose across many PFAS, in the absence of effects data linked to internal dose, would require more toxicokinetic data than are currently available.
Elimination half-lives can vary by PFAS structure chain length and degree of branching , across species, and by sex.
Because of this, grouping for the purpose of wildlife protection should be based on first identifying the most sensitive species and sex. For humans, translation of animal data would require two key pieces of information: first, whether the internal dose effect level is the same, and, second, the toxicokinetic data and associated model required to translate the effective internal dose in the human back to an external dose that can be associated with an exposure medium e.
Finally, the RPF approach may be difficult to reconcile for substances that have the potential to biotransform; should the parent compound, the metabolite, or both be considered in the calculation? In each case, is there a temporal component that needs to be taken into account, in addition to the toxicokinetic considerations suggested above?
For example, cellular assays suggest that reactive intermediate degradation products of fluorotelomer alcohols, such as short-chain saturated and unsaturated fluorotelomer aldehydes, are more toxic than either the parent compound or the terminal PFCA transformation products. The specific RPF approach suggested by RIVM is sound if it can be argued that liver hypertrophy is a sensitive and reliable endpoint for all PFAAs; a problem here is that many regulatory jurisdictions disagree with that assessment.
However, a similar additive toxicity approach could potentially be applied for those other endpoints. Expanding this knowledge base would require a large number of animal experiments and associated ethical considerations, time and money.
Within the universe of PFAS, most research to date has focused on the occurrence and effects of certain PFAAs and their precursors due to the availability of analytical methods and standards for these substances. Expanding beyond this domain has been challenging because the chemical composition of most remaining commercial products is unknown.
These factors are slowly becoming less of a barrier for identifying overlooked and unknown PFAS due to the recent advancement of non- and suspect-targeted screening techniques. Depending on the grouping strategies to be taken by individual regulatory agencies and companies, there will inevitably be efforts in the coming years to generate the missing data for some of the thousands of PFAS.
The new toxicity and toxicokinetic data generated from this initiative will support the development of quantitative structure—activity relationships QSARs that could facilitate filling data gaps, as well as further grouping and prioritization of the universe of PFAS.
There are clearly relationships between PFAS structural elements and properties and behaviour e. Within the EU, there is already discussion to phase out all non-essential uses of PFAS based on concerns of the chemical class as a whole.
Toxicological Effects of Perfluoroalkyl and Polyfluoroalkyl Substances
Perfluoroalkyl acids PFAAs , a group of synthetic organic chemicals with industrial and commercial uses, are of current concern because of increasing awareness of their presence in drinking water and their potential to cause adverse health effects. PFAAs are distinctive among persistent, bioaccumulative, and toxic PBT contaminants because they are water soluble and do not break down in the environment. This commentary discusses scientific and risk assessment issues that impact the development of drinking water guidelines for PFAAs, including choice of toxicological endpoints, uncertainty factors, and exposure assumptions used as their basis. In experimental animals, PFAAs cause toxicity to the liver, the immune, endocrine, and male reproductive systems, and the developing fetus and neonate. Low-dose effects include persistent delays in mammary gland development perfluorooctanoic acid; PFOA and suppression of immune response perfluorooctane sulfonate; PFOS. In humans, even general population level exposures to some PFAAs are associated with health effects such as increased serum lipids and liver enzymes, decreased vaccine response, and decreased birth weight. Ongoing exposures to even relatively low drinking water concentrations of long-chain PFAAs substantially increase human body burdens, which remain elevated for many years after exposure ends.
The combined effects and toxicological interactions of perfluoroalkyl and polyfluoroalkyl substances PFAS mixtures remain largely unknown even though they occur as complex mixtures in the environment. The Combination Index CI -isobologram equation method was used to determine the toxicological interactions of PFAS in binary, ternary and multi-component mixtures. The results indicated that the cytotoxicity of individual PFAS to HepG2 cells increased with increasing carbon chain lengths when separated into non-sulfonated and sulfonated groups. These cytotoxicity results may have an implication on the health risk assessment of PFAS mixtures.
This section provides reviews from a variety of sources on the toxicology human and ecological of PFASs. Individual specific studies are not called out but can be found in the extensive bibliographies of the resources listed.