Domestic Substances List Research Articles

Update and Evaluation of a High-Throughput In Vitro Mass Balance Distribution Model: IV-MBM EQP v2.0

This study demonstrates the utility of an updated mass balance model for predicting the distribution of organic chemicals in in vitro test systems (IV-MBM EQP v2.0) and evaluates its performance with empirical data. The IV-MBM EQP v2.0 tool was parameterized and applied to four independent data sets with measured ratios of bulk medium or freely-dissolved to initial nominal concentrations (e.g., C24/C0 where C24 is the measured concentration after 24 h of exposure and C0 is the initial nominal concentration). Model performance varied depending on the data set, chemical properties (e.g., “volatiles” vs. “non-volatiles”, neutral vs. ionizable organics), and model assumptions but overall is deemed acceptable. For example, the r2 was greater than 0.8 and the mean absolute error (MAE) in the predictions was less than a factor of two for most neutral organics included. Model performance was not as good for the ionizable organic chemicals included but the r2 was still greater than 0.7 and the MAE less than a factor of three. The IV-MBM EQP v2.0 model was subsequently applied to several hundred chemicals on Canada’s Domestic Substances List (DSL) with nominal effects data (AC50s) reported for two in vitro assays. We report the frequency of chemicals with AC50s corresponding to predicted cell membrane concentrations in the baseline toxicity range (i.e., >20–60 mM) and tabulate the number of chemicals with “volatility issues” (majority of chemical in headspace) and “solubility issues” (freely-dissolved concentration greater than water solubility after distribution). In addition, the predicted “equivalent EQP blood concentrations” (i.e., blood concentration at equilibrium with predicted cellular concentration) were compared to the AC50s as a function of hydrophobicity (log octanol-water partition or distribution ratio). The predicted equivalent EQP blood concentrations exceed the AC50 by up to a factor of 100 depending on hydrophobicity and assay conditions. The implications of using AC50s as direct surrogates for human blood concentrations when estimating the oral equivalent doses using a toxicokinetic model (i.e., reverse dosimetry) are then briefly discussed.

Implementing in vitro bioactivity data to modernize priority setting of chemical inventories.

Internationally, there are thousands of existing and newly introduced chemicals in commerce, highlighting the ongoing importance of innovative approaches to identify emerging chemicals of concern. For many chemicals, there is a paucity of hazard and exposure data. Thus, there is a crucial need for efficient and robust approaches to address data gaps and support risk-based prioritization. Several studies have demonstrated the utility of in vitro bioactivity data from the ToxCast program in deriving points of departure (PODs). ToxCast contains data for nearly 1,400 endpoints per chemical, and the bioactivity concentrations, indicative of potential adverse outcomes, can be converted to human-equivalent PODs using high-throughput toxicokinetics (HTTK) modeling. However, data gaps need to be addressed for broader application: the limited chemical space of HTTK and quantitative high-throughput screening data. Here we explore the applicability of in silico models to address these data needs. Specifically, we used ADMET predictor for HTTK predictions and a generalized read-across approach to predict ToxCast bioactivity potency. We applied these models to profile 5,801 chemicals on Canada’s Domestic Substances List (DSL). To evaluate the approach’s performance, bioactivity PODs were compared with in vivo results from the EPA Toxicity Values database for 1,042 DSL chemicals. Comparisons demonstrated that the bioac­tivity PODs, based on ToxCast data or read-across, were conservative for 95% of the chemicals. Comparing bioactivity PODs to human exposure estimates supports the identification of chemicals of potential interest for further work. The bioac­tivity workflow shows promise as a powerful screening tool to support effective triaging of chemical inventories.

Integrated in silico and in vitro genotoxicity assessment of thirteen data-poor substances

The Canadian Domestic Substances List (DSL) contains chemicals that have not been tested for genotoxicity as their use pre-dates regulatory requirements. In the present study, (quantitative) structure-activity relationships ((Q)SAR) model predictions and in vitro tests were conducted for genotoxicity assessment of 13 data-poor chemicals from the DSL (i.e. CAS numbers 19286-75-0, 13676-91-0, 2478-20-8, 6408-20-8, 74499-36-8, 26694-69-9, 29036-02-0, 120-24-1, 84696-48-9, 4051-63-2, 5718-26-3, 632-51-9, and 600-14-6). First, chemicals were screened by (Q)SAR models in Leadscope® and OASIS TIMES; two chemicals were excluded from (Q)SAR as they are complex mixtures. Six were flagged by (Q)SAR as potentially mutagenic and were subsequently confirmed as mutagens using the Ames assay. Of nine chemicals with clastogenic (Q)SAR flags, eight induced micronuclei in TK6 cells. Benchmark dose analysis was used to evaluate the potency of the chemicals. Four chemicals were bacterial mutagens with similar potencies. Three chemicals were more potent in micronuclei induction than the prototype alkylating agent methyl methanesulfonate and three were equipotent to the mutagenic carcinogen benzo[a]pyrene in the presence of rat liver S9. Overall, 11 of the 13 DSL chemicals demonstrated at least one type of genotoxicity in vitro. This study demonstrates the application of genotoxic potency analysis for prioritizing further investigations.

Challenges and opportunities in the risk assessment of existing substances in Canada: lessons learned from the international community

The evaluation and regulation of chemical substances have undergone a major overhaul in Canada, the USA and the European Union (EU) over the last decade. To facilitate increasing concerns over chemical safety, changes in regulations and strategic plans were introduced. Specifically, the Canadian parliament adopted a new amendment to the Canadian Environmental Protection Act (CEPA) in 1999, the US National Academy of Sciences published the 2007 NRC report TT21C, the US EPA developed the Strategic Plan in 2009, and the EU introduced new legislation in 2007 called Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH substances). A 2013 workshop held in Ottawa (Risk Sciences International) focused on regulatory issues and challenges faced by these nations. This review summarises many of the discussions held during the workshop and specifically, five challenges that Canada has encountered when assessing chemicals with limited data on Canada's Domestic Substances List (DSL).

Ecological Risk Assessments of Metal-containing Substances under Canada’s Chemical Management Plan

There are approximately 3,000 metal-containing substances on Canada's Domestic Substances List (DSL). Approximately one third of these substances were identified for further action by the categorization of the DSL, a priority setting exercise completed in 2006 which was based on ecological and human health considerations. Subsequently, the first phase of the Chemicals Management Plan (CMP) was initiated and included activities such as the Challenge initiative to conduct screening assessments on the highest priority chemicals, including a few metal-containing substances. However, to assess the remaining elevated number of metal-containing substances identified as priorities (~1000) in the next phases of the CMP and that by 2020, a process for finding efficiencies was established. For the risk assessment and risk management of metal-containing substances, efficiencies can be achieved by using a moiety-based approach in which all substances that contain a common metal moiety are assessed simultaneously as a group. This approach also allows for consideration of incidental releases of a given metal. Because ecological concerns were identified during the Challenge for cobalt, an early metal-moiety assessment is being undertaken in the second phase of the CMP for this metal. This work has been initiated and the draft screening assessment is expected to be published in November 2013.

Screening Criteria for Long-Range Transport Potential of Organic Substances in Water

Screening of long-range transport potential (LRTP) of organic chemicals in water requires the development of criteria in analogy to the existing LRTP criteria for airborne chemicals. According to the Stockholm Convention, compounds mainly partitioning into air are assumed to be prone to LRTP if they have a half-life in air of more than two days. Using mean flow velocities of European rivers (0.7-1 m/s) and of ocean currents running into the Arctic Ocean (0.28-0.9 m/s), we derived corresponding half-life criteria for freshwater and seawater (10 days and 90 days, respectively). Next, we calculated the characteristic travel distance (CTD) of several thousand chemicals from the Canadian Domestic Substances List (DSL) and all current POPs using the multimedia model ELPOS. This shows that the CTD in water dominates the CTD in air only for chemicals that are characterized by a large half-life in water and a low air-water partition coefficient (about 38% of the nonionic organic substances selected from the DSL). In particular, there are substances that are not classified as persistent compounds in water but exhibit higher CTDs for transport in water than for transport in air. Finally, we evaluated whether the LRTP boundary derived from POP reference chemicals has to be revised if LRTP in water is included and found that this boundary can be applied to all organic chemicals regardless of their transport in air or water.

Dow and Kaw,eff vs. Kow and K°aw: Acid/base ionization effects on partitioning properties and screening commercial chemicals for long-range transport and bioaccumulation potential

A set of 543 ionizable commercial organic compounds with various acid/base functionalities and experimental octanol-water partitioning coefficients (log Kow) were obtained from the Canadian Domestic Substances List. Corresponding pH-dependent octanol-water distribution coefficients (log Dow) and air-water partitioning coeffients (log Kaw,eff) were estimated using the SPARC software program, as were log Kow and log K°aw values for the neutral forms of each chemical. Significant ionization dependent effects on chemical screening results at various pH values were obtained using established criteria for bioaccumulation potential (BAP) in aquatic organisms, terrestrial animals, and humans, as well as for atmospheric long range transport potential (LRTP). Future modelling efforts for environmental and toxicological screening of commercial chemicals should therefore explicitly include the influence of ionization for both weak and strong organic acids and bases on bioavailability and air-water mobility within the respective regulatory frameworks. Functional group specific sorption of both ionizable and neutral compounds to particulate and dissolved inorganic and organic matter will also affect chemical screening results for BAP and LRTP. More complex sorption related modelling in various types of representative aquatic systems also appears necessary to achieve reliable chemical screening results for commercial organic compounds.

Performance of the ALOGPS 2.1 program for octanol-water partition coefficient prediction with organic chemicals on the Canadian Domestic Substances List

AbstractThe KOWWIN and ALOGPS octanol-water partition coefficient (K~ow~) estimation software programs were compared for their capacity to accurately predict log K~ow~ values of 1545 organic compounds on the publicly available Domestic Substances List (DSL) from Environment Canada for which experimental data is available. Approximately equivalent log K~ow~ error statistics were observed between KOWWIN and ALOGPS against available experimental data. Substantial predictive differences were observed between the two programs for 6529 compounds not having experimental K~ow~ data on the Canadian DSL. Predictive differences of up to 40 log K~ow~ units were found between KOWWIN and ALOGPS, and in some cases, the discrepancies were sufficiently large that strongly opposing hydrophobicity classifications were obtained.

Performance of the ALOGPS 2.1 program for octanol-water partition coefficient prediction with organic chemicals on the Canadian Domestic Substances List

The KOWWIN and ALOGPS octanol-water partition coefficient (K~ow~) estimation software programs were compared for their capacity to accurately predict log K~ow~ values of 1545 organic compounds on the publicly available Domestic Substances List (DSL) from Environment Canada for which experimental data is available. Approximately equivalent log K~ow~ error statistics were observed between KOWWIN and ALOGPS against available experimental data. Substantial predictive differences were observed between the two programs for 6529 compounds not having experimental K~ow~ data on the Canadian DSL. Predictive differences of up to 40 log K~ow~ units were found between KOWWIN and ALOGPS, and in some cases, the discrepancies were sufficiently large that strongly opposing hydrophobicity classifications were obtained.

Determining the maximum environmental release limit of the toxic dye, CHPD

The Canadian Environmental Protection Act, 1999 (CEPA, 1999) requires the Canadian government to categorize all substances on the Domestic Substances List (DSL). Under the Chemicals Management Plan, the Government of Canada addresses chemicals that had not previously undergone rigorous scientific assessment. One such compound, [[4-[[2-(4-cyclohexylphenoxy)ethyl]ethylamino]-2-methylphenyl]methylene]-, propanedinitrile, commonly known as CHPD (cyclohexylphenoxydinitrile), recently underwent a screening assessment and was declared to be “toxic” to the environment. As a result, the Government of Canada ordered the “virtual elimination” of CHPD from the environment. Thus, CHPD may not be present above the lowest concentration that can be accurately measured using sensitive, but routine, analytical methods. We present a solid-phase extraction (SPE) method to determine CHPD in water and wastewater effluent to establish the maximum environmental release limit for this toxic compound. Optimal extraction was attained using an ENVI-18 cartridge. Extracts were analyzed by HPLC–PDA and HPLC–MS/MS techniques; in both matrices, the PDA method had greater sensitivity, less susceptibility to matrix effects, lower limit of quantitation (LOQ) values, and could be successfully validated at multiple spike levels. The lowest concentration of CHPD that could accurately be measured was found to be 108 ng/L in extracts of pure water, using the HPLC–PDA system. Therefore, this value (108 ng/L) will inform regulations on the maximum environmental release limit for CHPD.

Performance of the ALOGPS 2.1 program for octanol-water partition coefficient prediction with organic chemicals on the Canadian Domestic Substances List

AbstractThe KOWWIN and ALOGPS octanol-water partition coefficient (K~ow~) estimation software programs were compared for their capacity to accurately predict log K~ow~ values of 1596 organic compounds on the publicly available Domestic Substances List (DSL) from Environment Canada for which experimental data is available. KOWWIN contained a significantly lower number and magnitude of prediction errors compared to ALOGPS, particularly at experimental log K~ow~ values <2. Substantial predictive differences were observed between the two programs for 9093 compounds not having experimental K~ow~ data on the Canadian DSL. Predictive differences of up to 40 log K~ow~ units were found between KOWWIN and ALOGPS, and in some cases, the discrepancies were sufficiently large that strongly opposing hydrophobicity classifications were obtained.

Tools for the prioritization of substances on the Domestic Substances List in Canada on the basis of hazard

A precedent setting legislative mandate under the Canadian Environmental Protection Act 1999 to establish priorities for assessment based on systematic consideration of all of the approximately 23,000 Existing Chemicals in Canada required the development and refinement of methodology in a number of important areas. This included development of simple and complex exposure and hazard tools for priority setting which draw maximally and efficiently on available data to systematically identify substances that are highest priorities in relation to their potential to cause adverse effects on the general population. The hierarchical approach in the simple and complex hazard tools described here efficiently and effectively sets substances aside as non-priorities, or prioritizes them for consideration additionally in assessment. The hazard tools efficiently incorporate previous work, contributing to consistency internationally, and involve hierarchical consideration of sources of information based on their relative weighting. They are health protective, based on their incorporated degree of conservatism, and provide direction for additional assessment for substances deemed to be priorities. Although designed for prioritization of Existing Substances in Canada, these tools have potential for broader application in other national and international programs to provide focus and increase efficiency in human health risk assessment.

Screening the partition behavior of a large number of chemicals with a quantum-chemical software

For 8500 organic chemicals from the Canadian Domestic Substances List, air/water and octanol/water partition coefficients have been calculated with COSMO frag a predictive a priori method based on quantum mechanics and statistical thermodynamics provided by COSMO logic. The results were compared with predictions from the EPI Suite™. On average a difference of 1.8 log units between both methods was observed for the predicted log K aw values. This has consequences for the classification in terms of atmospheric long range transport potential and bioaccumulation in the terrestrial food chain where 11% and 17% of all compounds were classified differently. Much better agreement was observed for the predicted log K ow. Principal differences became obvious for compounds that occur as isomers or conformers. The modules of the EPI Suite™ are not designed to account for information on stereochemistry of molecules or E/Z isomers. Intramolecular H-bonds are only accounted for if specific correction factors exist from the calibration procedure. In contrast, COSMO frag in combination with COSMO therm can identify the existence of such isomers or H-bond conformers and account for these effects in the calculations.

Policies for Chemical Hazard and Risk Priority Setting: Can Persistence, Bioaccumulation, Toxicity, and Quantity Information Be Combined?

Existing methods used to screen chemical inventories for hazardous substances that may pose risks to humans and the environment are evaluated with a holistic mass balance modeling approach. The model integrates persistence (P), bioaccumulation (B), toxicity (T), and quantity (Q) information for a specific substance to assess chemical exposure, hazard, and risk. P and B are combined in an exposure assessment factor (EAF), P, B, and T in a hazard assessment factor (HAF), and P, B, T, and Q in a risk assessment factor (RAF) providing single values for transparent comparisons of exposure, hazard, and risk for priority setting. This holistic approach is illustrated using 200 Canadian Domestic Substances List(DSL) chemicals and 12 United Nations listed Persistent Organic Pollutants (POPs). Priority setting results are evaluated with those of multiple category-based screening methods employed by Environment Canada and applied elsewhere that use cutoff criteria in multiple categories (P, B, and T) to identify hazardous chemicals for more comprehensive evaluations. Existing methods have categorized the DSL chemicals as either higher priority (requiring further assessment; screened in) or lower priority (requiring no further action at this time; screened out). The priority setting results of the cutoff-based categorization are largely inconsistent with the proposed integrated method, and reasons for these discrepancies are discussed. Many chemicals screened out using existing methods have equivalent or greater risk potential than chemicals screened in. Decisions for screening assessments using binary classification on the basis of cutoff criteria can be flawed, and complementary holistic methods for priority setting evaluations such as the one proposed should be considered.

Integrated approach to assess the domain of applicability of some commercial (Q)SAR models1

An integrated framework of data analysis has been proposed to systematically address the determination of the domain of applicability (DA) of some commercial Quantitative Structure Activity Relationship ((Q)SAR) models based on the structure of test chemicals. This framework forms one of the important steps in dealing with the growing concerns on reliability of model-based predictions on toxicity of chemicals specifically in the regulatory context. The present study uses some of the well-known mutagenicity and carcinogenicity models that are available within the Casetox (MultiCASE Inc.) and TOPKAT (Accelrys Software Inc.) programs. The approach enumerated in this paper employs chemoinformatics tools that facilitate comparisons of key structural features as well as application of cluster analysis techniques. The approach has been illustrated using a set of eleven chemical structures selected from the Canadian Domestic Substances List (DSL) that are not present in the model training sets, and the efficacy of the approach has also been assessed using seven chemicals with known toxicities. The methodologies presented here could help address the issue of DA of complex (Q)SAR models and at the same time, serve as useful tools for regulators to make a preliminary assessment of (Q)SAR based systems thereby helping the process of hazard-based regulatory assessments of chemicals. 1Presented at CMTPI 2007: Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (Moscow, Russia, September 1–5, 2007).

A review of bioconcentration factor (BCF) and bioaccumulation factor (BAF) assessments for organic chemicals in aquatic organisms

Bioaccumulation assessment is important in the scientific evaluation of risks that chemicals may pose to humans and the environment and is a current focus of regulatory effort. The status of bioaccumulation evaluations for organic chemicals in aquatic systems is reviewed to reduce uncertainty in bioaccumulation measurement, to provide quality data for assessment, and to assist in model development. A review of 392 scientific literature and database sources includes 5317 bioconcentration factor (BCF) and 1656 bioaccumulation factor (BAF) values measured for 842 organic chemicals in 219 aquatic species. A data quality assessment finds that 45% of BCF values are subject to at least one major source of uncertainty and that measurement errors generally result in an underestimation of actual BCF values. A case study of organic chemicals on the Canadian Domestic Substances List indicates that empirical data are available for less than 4% of the chemicals that require evaluation and of these chemicals, 76% have less than three acceptable quality BCF or BAF values. Field BAFs tend to be greater than laboratory BCFs emphasizing the importance of environmental measurement for reliable assessment; however, only 0.2% of current use organic chemicals have BAF measurements. Key parameters influencing uncertainty and variability in BCF and BAF data are discussed using reviewed data and models. A critical evaluation of representative BCF and BAF models in relation to existing measurements and regulatory criteria in Canada indicate the probability of Type II errors, i.e., false negatives or ``misses'', using BCF models for bioaccumulation assessment may be as high as 70.6% depending on the model. Recommendations for the selection of measured and modelled values used in bioaccumulation assessment are provided, and improvements for the science and regulatory criteria are proposed.Key words: bioconcentration, bioconcentration factor, bioaccumulation, bioaccumulation factor, octanol–water partition coefficient, fish.

Are There Other Persistent Organic Pollutants? A Challenge for Environmental Chemists

The past 5 years have seen some major successes in terms of global measurement and regulation of persistent, bioaccumulative, and toxic (PB&T) chemicals and persistent organic pollutants (POPs). The Stockholm Convention, a global agreement on POPs, came into force in 2004. There has been a major expansion of measurements and risk assessments of new chemical contaminants in the global environment, particularly brominated diphenyl ethers and perfluorinated alkyl acids. However, the list of chemicals measured represents only a small fraction of the approximately 30,000 chemicals widely used in commerce (>1 t/y). The vast majority of existing and new chemical substances in commerce are not monitored in environmental media. Assessment and screening of thousands of existing chemicals in commerce in the United States, Europe, and Canada have yielded lists of potentially persistent and bioaccumulative chemicals. Here we review recent screening and categorization studies of chemicals in commerce and address the question of whether there is now sufficient information to permit a broader array of chemicals to be determined in environmental matrices. For example, Environment Canada's recent categorization of the Domestic (existing) Substances list, using a wide array of quantitative structure activity relationships for PB&T characteristics, has identified about 5.5% of 11,317 substances as meeting P & B criteria. Using data from the Environment Canada categorization, we have listed, for discussion purposes, 30 chemicals with high predicted bioconcentration and low rate of biodegradation and 28 with long range atmospheric transport potential based on predicted atmospheric oxidation half-lives >2 days and log air-water partition coefficients > or =5 and < or =1. These chemicals are a diverse group including halogenated organics, cyclic siloxanes, and substituted aromatics. Some of these chemicals and their transformation products may be candidates for future environmental monitoring. However, to improve these predictions data on emissions from end use are needed to refine environmental fate predictions, and analytical methods may need to be developed.

Consumer Exposure Scenarios in the Health Canada Existing Substances Program

TS1-13 Abstract: Canada is the first country to introduce a legislative requirement for systematic priority setting for all existing chemicals. In addition to a continuing mandate to establish and conduct full assessments for lists of priority substances, the Canadian Environmental Protection Act (CEPA '99) requires that the Ministers of Health and Environment complete “categorization” (priority setting) of all of the approximately 23,000 substances on the Domestic Substances List (DSL) by September 2006, with subsequent screening and full risk assessment, when warranted. These requirements set the stage for identification of highest priority substances for subsequent introduction of control measures to reduce exposure in both consumer products and the general environment. This precedent setting mandate has required the development and refinement of methodology for priority setting and risk assessment for a wide range of diverse substances. These approaches draw maximally from available, often generic information as a basis to consider large numbers of substances, for which individual data on exposure and hazard are often limited. Estimation of exposure to consumer products is addressed both in priority setting and assessment stages of the program. For consumer products, an approach has been developed to provide quantitative estimates of exposure relevant in a priority setting context. This has required consideration of the relative degree of conservatism in existing exposure modeling algorithms and development of a considerable number of additional scenarios and leads to quantitative plausible maximum estimates of exposure of individuals in the general population by age group based on use scenario, physical/chemical properties, and bioavailability. Comparison of the output with measures of exposure–response for relevant critical effects leads to substances being set aside from further consideration or prioritized for additional assessment. After 2006, the approach will also contribute to efficient screening, delineating the focus of subsequent assessment. The development and integration of consumer exposure modeling in increasingly broad legislative mandates to systematically consider all existing chemicals raises a number of issues relevant to exposure assessment in differing jurisdictions. These include transparency, consistency, usability, and defensibility of the models, including relevant degree of complexity for priority setting versus assessment. These issues are discussed through examples and lessons learned from the development of the approach to consumer products for priority setting and screening assessment.

Screening Level Risk Assessment Model for Chemical Fate and Effects in the Environment

A screening level risk assessment model is developed and described to assess and prioritize chemicals by estimating environmental fate and transport, bioaccumulation, and exposure to humans and wildlife for a unit emission rate. The most sensitive risk endpoint is identified and a critical emission rate is then calculated as a result of that endpoint being reached. Finally, this estimated critical emission rate is compared with the estimated actual emission rate as a risk assessment factor. This "back-tracking" process avoids the use of highly uncertain emission rate data as model input. The application of the model is demonstrated in detail for three diverse chemicals and in less detail for a group of 70 chemicals drawn from the Canadian Domestic Substances List. The simple Level II and the more complex Level III fate calculations are used to "bin" substances into categories of similar probable risk. The essential role of the model is to synthesize information on chemical and environmental properties within a consistent mass balance framework to yield an overall estimate of screening level risk with respect to the defined endpoint. The approach may be useful to identify and prioritize those chemicals of commerce that are of greatest potential concern and require more comprehensive modeling and monitoring evaluations in actual regional environments and food webs.

Predicting the biodegradation products of perfluorinated chemicals using CATABOL

Perfluorinated chemicals (PFCs) form a special category of organofluorine compounds with particularly useful and unique properties. Their large use over the past decades increased the interest in the study of their environmental fate. Fluorocarbons may have direct or indirect environmental impact through the products of their decomposition in the environment. It is a common knowledge that biodegradation is restricted within non-perfluorinated part of molecules; however, a number of studies showed that defluorination can readily occur during biotransformation. To evaluate the fate of PFCs in the environment a set of principal transformations was developed and implemented in the simulator of microbial degradation using the catabolite software engine (CATABOL). The simulator was used to generate metabolic pathways for 171 perfluorinated substances on Canada's domestic substances list. It was found that although the extent of biodegradation of parent compounds could reach 60%, persistent metabolites could be formed in significant quantities. During the microbial degradation a trend was observed where PFCs are transformed to more bioaccumulative and more toxic products. Perfluorooctanoic acid and perfluorooctanesulfonate were predicted to be the persistent biodegradation products of 17 and 27% of the perfluorinated sulphonic acid and carboxylic acid containing compounds, respectively.