updated COU

exposure3_module/static/exposure_COU.html

@@ -63,18 +63,25 @@ conformance to the underlying assumptions or provide supporting
 justification to ensure compliance for a given system. Further, CHRIS
 only enables system specific exposure estimates for fifty-three (53)
 polymeric systems that are generally biostable (non-swelling and
-non-degrading). These polymers are listed below. To estimate chemical
-release based on the model, the diffusion coefficient of the chemical in
-the polymer matrix must be specified. For the fifty-three (53) listed
-polymeric systems, a worst-case (upper bound) diffusion coefficient, as
-a function of molecular weight, has been established based on data from
-the literature. For polymer matrices that are not included in this list,
-CHRIS assigns an ultra-conservative diffusion coefficient that assumes
-the polymer has the properties of water. Note that the worst-case
-diffusion coefficient is only defined over a molecular weight range of
-up to 1100 g/mol. Therefore, for substances with a molecular weight >
-1100 g/mol, the value of the diffusion coefficient assuming a molecular
-weight of 1100 g/mol can be used as a conservative value.</p>
+non-degrading). To estimate chemical release based on the model, the
+diffusion coefficient of the chemical in the polymer matrix must be
+specified. For the fifty-three (53) listed polymeric systems, a
+worst-case (upper bound) diffusion coefficient, as a function of
+molecular weight, has been established based on data from the
+literature. For polymer matrices that are not included in this list
+(“Other polymer”), CHRIS has two approaches. If the polymer glass
+transition temperature is not specified, an ultra-conservative diffusion
+coefficient that assumes the polymer has the properties of water is
+used. However, if the glass transition temperature is specified, a
+less-conservative upper bound diffusion coefficient is estimated using a
+machine learning method. Note that the worst-case diffusion coefficient
+is only defined over a molecular weight range of up to 1100 g/mol.
+Therefore, for substances with a molecular weight &gt; 1100 g/mol, the
+value of the diffusion coefficient assuming a molecular weight of 1100
+g/mol is used as a conservative value. If the machine learning method is
+used to estimate the diffusion coefficient, a warning is issued if the
+polymer/solute combination falls outside the domain of the training
+data, indicating that the prediction may not be reliable.</p>
 <p>In the absence of adequate toxicological and exposure data for a
 chemical in a polymeric matrix, a toxicological risk assessment can be
 conducted for systemic biocompatibility endpoints by comparing the

exposure3_module/static/exposure_COU.md

@@ -29,6 +29,6 @@ CHRIS provides clinically relevant, yet still conservative, exposure dose estima
 1. The total amount of the chemical is present in dilute concentrations (<= 2 m/v %).
 1. Any particles/aggregates of the chemical present in the polymer are much smaller than the smallest component dimension (<= 50x).
 
-While these assumptions are typically valid for bulk additives and impurities in biostable polymers, users of CHRIS must confirm conformance to the underlying assumptions or provide supporting justification to ensure compliance for a given system.  Further, CHRIS only enables system specific exposure estimates for fifty-three (53) polymeric systems that are generally biostable (non-swelling and non-degrading).  These polymers are listed below.  To estimate chemical release based on the model, the diffusion coefficient of the chemical in the polymer matrix must be specified.  For the fifty-three (53) listed polymeric systems, a worst-case (upper bound) diffusion coefficient, as a function of molecular weight, has been established based on data from the literature.  For polymer matrices that are not included in this list, CHRIS assigns an ultra-conservative diffusion coefficient that assumes the polymer has the properties of water.  Note that the worst-case diffusion coefficient is only defined over a molecular weight range of up to 1100 g/mol.  Therefore, for substances with a molecular weight > 1100 g/mol, the value of the diffusion coefficient assuming a molecular weight of 1100 g/mol can be used as a conservative value.
+While these assumptions are typically valid for bulk additives and impurities in biostable polymers, users of CHRIS must confirm conformance to the underlying assumptions or provide supporting justification to ensure compliance for a given system.  Further, CHRIS only enables system specific exposure estimates for fifty-three (53) polymeric systems that are generally biostable (non-swelling and non-degrading).  To estimate chemical release based on the model, the diffusion coefficient of the chemical in the polymer matrix must be specified.  For the fifty-three (53) listed polymeric systems, a worst-case (upper bound) diffusion coefficient, as a function of molecular weight, has been established based on data from the literature.  For polymer matrices that are not included in this list ("Other polymer"), CHRIS has two approaches.  If the polymer glass transition temperature is not specified, an ultra-conservative diffusion coefficient that assumes the polymer has the properties of water is used.  However, if the glass transition temperature is specified, a less-conservative upper bound diffusion coefficient is estimated using a machine learning method.  Note that the worst-case diffusion coefficient is only defined over a molecular weight range of up to 1100 g/mol.  Therefore, for substances with a molecular weight > 1100 g/mol, the value of the diffusion coefficient assuming a molecular weight of 1100 g/mol is used as a conservative value.  If the machine learning method is used to estimate the diffusion coefficient, a warning is issued if the polymer/solute combination falls outside the domain of the training data, indicating that the prediction may not be reliable.
 
 In the absence of adequate toxicological and exposure data for a chemical in a polymeric matrix, a toxicological risk assessment can be conducted for systemic biocompatibility endpoints by comparing the exposure estimate to an appropriate threshold of toxicological concern (TTC).  This is the approach used by CHRIS in this module. The TTC values are based on systemic toxicity, thus CHRIS can address acute systemic toxicity, subacute/subchronic toxicity, genotoxicity, carcinogenicity, and reproductive and developmental toxicity.  It does not, however, address cytotoxicity, sensitization, irritation, hemocompatibility, material mediated pyrogenicity, or implantation. Therefore, an MOS >= 1 implies the chemical will not raise a safety concern with respect to only the systemic biocompatibility endpoints, provided the chemical is not within the cohort of concern, which is reflected in the output of CHRIS.