R Under development (unstable) (2023-12-07 r85661 ucrt) -- "Unsuffered Consequences"
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> # R CMD BATCH --no-timing --no-restore --no-save montecarlo_tests.R montecarlo_tests.Rout
> 
> # Get rid of anything in the workspace:
> rm(list=ls()) 
> 
> library(httk)
> 
> # Reduce the number of samples used by Monte Carlo to decrease runtime for
> # CRAN checks (never use predictions with only ten draws):
> NSAMP <- 10
> 
> #
> #
> # Test that the underlying PK models give the same answers:
> calc_analytic_css(chem.cas="15972-60-8")
Plasma concentration returned in uM units.
[1] 0.2299
Warning messages:
1: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) :
  Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu.
2: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
3: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment,  :
  Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction.
4: In available_rblood2plasma(chem.cas = chem.cas, species = species,  :
  Human in vivo measured Rblood2plasma used.
5: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> calc_analytic_css(chem.cas="15972-60-8",model="1compartment")
Human volume of distribution returned in units of L/kg BW.
Plasma concentration returned in uM units.
[1] 0.2695
Warning messages:
1: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
2: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment,  :
  Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction.
3: In available_rblood2plasma(chem.cas = chem.cas, chem.name = chem.name,  :
  Human in vivo measured Rblood2plasma used.
> calc_analytic_css(chem.cas="15972-60-8",model="pbtk")
Plasma concentration returned in uM units.
[1] 0.2299
Warning messages:
1: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) :
  Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu.
2: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
3: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment,  :
  Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction.
4: In available_rblood2plasma(chem.cas = chem.cas, species = species,  :
  Human in vivo measured Rblood2plasma used.
5: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> calc_analytic_css(chem.cas="15972-60-8",model="3compartment")
Plasma concentration returned in uM units.
[1] 0.2703
Warning messages:
1: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) :
  Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu.
2: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
3: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment,  :
  Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction.
4: In available_rblood2plasma(chem.cas = chem.cas, species = species,  :
  Human in vivo measured Rblood2plasma used.
5: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> 
> 
> 
> #
> #
> # Now test Monte Carlo for a variety of chemicals:
> # Clint and Fup are distributions, clint is zero:
> set.seed(1234)
> uM <- calc_mc_css(chem.cas="50594-66-6",samples=NSAMP,output.units="uM")
Human plasma concentration returned in uM units for 0.95 quantile.
Warning messages:
1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Clint is provided as a distribution.
2: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Fraction unbound is provided as a distribution.
3: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Clint is provided as a distribution.
> set.seed(1234)
> mgpL <- calc_mc_css(chem.cas="50594-66-6",samples=NSAMP,output.units="mg/L")
Human plasma concentration returned in mg/L units for 0.95 quantile.
Warning messages:
1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Clint is provided as a distribution.
2: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Fraction unbound is provided as a distribution.
3: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Clint is provided as a distribution.
> # Test unit conversions, molecular weight of Acifluorfen is 361.66:
> signif(mgpL/uM*1000,4)
  95% 
361.6 
> # Human.Clint.pvalue > 0.05, no measured Rblood2plasma
> set.seed(1234)
> calc_mc_css(chem.cas="116-06-3",samples=NSAMP)
Human plasma concentration returned in mg/L units for 0.95 quantile.
  95% 
6.206 
Warning message:
In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> # Human.Funbound.plasma is below LOD (0.005), can't do PBPK, can't predict
> # Rblood2plasma
> set.seed(1234)
> calc_mc_css(chem.cas="101-05-3",samples=NSAMP)
Human plasma concentration returned in mg/L units for 0.95 quantile.
 95% 
22.4 
Warning messages:
1: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Fraction unbound below limit of detection.
2: In (function (chem.cas = NULL, chem.name = NULL, dtxsid = NULL,  :
  Fraction unbound = 0, changed to 0.005.
3: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> # well-behaved chemical with a measured Rblood2plasma:
> set.seed(1234)
> calc_mc_css(chem.cas="15972-60-8",samples=NSAMP)
Human plasma concentration returned in mg/L units for 0.95 quantile.
   95% 
0.2433 
Warning message:
In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> # Chemical where median fup is 0 but upper 95th percentile is non-zero:
> set.seed(1234)
> calc_mc_css(dtxsid="DTXSID5041726",samples=NSAMP)
Human plasma concentration returned in mg/L units for 0.95 quantile.
 95% 
3751 
Warning messages:
1: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Fraction unbound is provided as a distribution.
2: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> 
> #
> #
> # Now test that MC works across different models:
> set.seed(1234)
> calc_mc_css(chem.cas="15972-60-8",model="3compartment",samples=NSAMP)
Human plasma concentration returned in mg/L units for 0.95 quantile.
   95% 
0.2438 
Warning messages:
1: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
2: In available_rblood2plasma(chem.cas = chem.cas, species = species,  :
  Human in vivo measured Rblood2plasma used.
3: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> set.seed(1234)
> calc_mc_css(chem.cas="15972-60-8",model="1compartment",samples=NSAMP)
Human volume of distribution returned in units of L/kg BW.
Human plasma concentration returned in mg/L units for 0.95 quantile.
   95% 
0.2434 
Warning messages:
1: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
2: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment,  :
  Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction.
3: In available_rblood2plasma(chem.cas = chem.cas, chem.name = chem.name,  :
  Human in vivo measured Rblood2plasma used.
> set.seed(1234)
> calc_mc_css(chem.cas="15972-60-8",model="pbtk",samples=NSAMP)
Human plasma concentration returned in mg/L units for 0.95 quantile.
   95% 
0.2075 
Warning messages:
1: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
2: In available_rblood2plasma(chem.cas = chem.cas, species = species,  :
  Human in vivo measured Rblood2plasma used.
3: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> 
> # Should be the same as the mean result:
> calc_analytic_css(chem.cas="90-43-7",model="pbtk",output.units="mg/L")
Plasma concentration returned in mg/L units.
[1] 11.27
Warning messages:
1: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) :
  Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu.
2: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment,  :
  Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction.
3: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment,  :
  Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction.
4: In calc_rblood2plasma(chem.cas = chem.cas, species = species, adjusted.Funbound.plasma = adjusted.Funbound.plasma,  :
  Rblood2plasma has been recalculated.
5: In available_rblood2plasma(chem.cas = chem.cas, species = species,  :
  Human Rblood2plasma calculated with calc_rblood2plasma.
6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> 
> set.seed(1234)
> # HTTK Monte Carlo using basic Monte Carlo sampler:
> calc_mc_css(chem.cas="90-43-7",
+   model="pbtk",
+   samples=NSAMP,
+   httkpop=FALSE,
+   invitrouv=FALSE,
+   vary.params=list(Pow=0.3))
Human plasma concentration returned in mg/L units for 0.95 quantile.
  95% 
9.151 
Warning messages:
1: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment,  :
  Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction.
2: In calc_rblood2plasma(chem.cas = chem.cas, species = species, adjusted.Funbound.plasma = adjusted.Funbound.plasma,  :
  Rblood2plasma has been recalculated.
3: In available_rblood2plasma(chem.cas = chem.cas, species = species,  :
  Human Rblood2plasma calculated with calc_rblood2plasma.
4: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> 
> 
> #set.seed(1234)    
> # well-behaved chemical with a measured Rblood2plasma:
> # lapply(calc_mc_tk(chem.cas="80-05-7",samples=NSAMP),function(x) x[-2,])
> 
> # make sure the oral equivalent function works:
> set.seed(1234)
> calc_mc_oral_equiv(chem.name="bisphenol a",conc=10,samples=NSAMP)
Human plasma concentration returned in uM units for 0.95 quantile.
uM concentration converted to mgpkgpday dose for 0.95 quantile.
  95% 
2.217 
Warning messages:
1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Clint is provided as a distribution.
2: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Fraction unbound is provided as a distribution.
3: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> set.seed(1234)
> # Do the calculation manually to make sure units are correct:
> signif(10/calc_mc_css(chem.name="bisphenol a",samples=NSAMP,output.units="uM"),4)
Human plasma concentration returned in uM units for 0.95 quantile.
  95% 
2.217 
Warning messages:
1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Clint is provided as a distribution.
2: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Fraction unbound is provided as a distribution.
3: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> 
> # do test of passing data.table of parameters
> set.seed(1234)
> parameter.dt <- create_mc_samples(chem.cas="335104-84-2",
+                                     model="pbtk",
+                                     samples=NSAMP)
Warning messages:
1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Clint is provided as a distribution.
2: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Fraction unbound is provided as a distribution.
4: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
5: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Fraction unbound is provided as a distribution.
6: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment,  :
  Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction.
7: In calc_rblood2plasma(chem.cas = chem.cas, species = species, adjusted.Funbound.plasma = adjusted.Funbound.plasma,  :
  Rblood2plasma has been recalculated.
8: In available_rblood2plasma(chem.cas = chem.cas, species = species,  :
  Human Rblood2plasma calculated with calc_rblood2plasma.
9: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> calc_mc_oral_equiv(conc=100,
+                    parameters=parameter.dt,
+                    model="pbtk")
Human plasma concentration returned in uM units for 0.95 quantile.
uM concentration converted to mgpkgpday dose for 0.95 quantile.
  95% 
1.396 
> 
> # If we turn off all the montecarlo the samples should all be the same and
> # give us the same result as calc_analytic_css:
> a <- calc_mc_css(
+   chem.cas = "80-05-7", 
+   output.units = "uM", 
+   model = "3compartmentss", 
+   species = "Human",
+   samples=NSAMP, 
+   httkpop=FALSE, 
+   invitrouv=FALSE, 
+   return.samples=TRUE)
Human plasma concentration returned in uM units.
Warning messages:
1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Clint is provided as a distribution.
2: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Fraction unbound is provided as a distribution.
3: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> b <- calc_analytic_css(
+   chem.cas = "80-05-7", 
+   output.units = "uM", 
+   model = "3compartmentss", 
+   species = "Human")
Plasma concentration returned in uM units.
Warning messages:
1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Clint is provided as a distribution.
2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) :
  Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu.
3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas,  :
  Fraction unbound is provided as a distribution.
4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment,  :
  Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction.
5: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
> all(a/b==1) 
[1] TRUE
>                    
> quit("no")
> proc.time()
   user  system elapsed 
  12.48    0.43   12.90