Infant's indirect exposure

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Question

How to measure infant's dioxin exposure due to fetal period and breast feeding?

Answer

Mother's exposure at level 100 pg /d (fairly typical amount) will lead to child's TEQ concentration of 44 pg /g fat (logTEQ 3.8).

+ Show code- Hide code # This is code Op_en7797/ on page [[Infant's dioxin exposure]] library(OpasnetUtils) objects.latest("Op_en7797", code_name="initiate") exposure <- Ovariable("exposure", data = data.frame(Exposure_agent = "TEQ", Result = 100)) dx.expo.child <- EvalOutput(dx.expo.child) oprint(summary(dx.expo.child))

Rationale

The equations and code below was developed for dioxins, but later it was extended to perfluorinated alkyl substances (PFAS) as well.

Transformation between serum concentration and intake:

Failed to parse (SVG (MathML can be enabled via browser plugin): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle C_s = \frac{I * t_{1/2} * f}{a * ln2 * BF%},}

where
Cs = serum concentration of compound in pg/g fat
I = average daily intake of compound in pg/kg/day
t1/2 = the half-life of compound (2737.5 d = 7.5 a)
f = fraction of ingested compound actually absorbing from the gut (0.80)
BF% = body fat percentage
a percentage of total daily dietary intake of compounds that come from fish (0.86).

The previous equation applies in a single individual. In the case of dental aberrations, the main exposure comes from the mother during pregnancy and breast feeding. For this, we use

Failed to parse (SVG (MathML can be enabled via browser plugin): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle C_{s,i} = \frac{I_{a,m} * t_{1/2,m} * f_m * FE}{ln2 * BF_i},}

where
Cs,i = serum concentration of compound in the infant in pg/g fat
Ia,m = average daily intake of compound of the mother in absolute amounts pg/day
t1/2,m = the half-life of compound in the mother (2737.5 d = 7.5 a)
fm = fraction of ingested compound actually absorbing from the gut in the mother (0.80)
FE = fraction of mother's compound load that is transported to the infant during breast feeding (0.25) Vartiainen et al. REF
BF = body fat amount in the infant (into which the compound is evenly distributed) during the period when tooth are sensitive to defects and the exposure at its highest (ca. six months of age) (1 kg)

With dioxin, body fat represents the distribution volume, as the compound distributes evenly in the fat compartments of the body. Therefore, the dioxin concentration per gram fat is approximately the same in blood and fat tissue. With PFAS, the concentration in blood equals total amount divided by the distribution volume.

Inputs

Parameters(-)

Obs	Exposure_agent	Parameter	Value	Description
1	TEQ	half-life	2737.5	t0.5: 7.5 * 365, Dioxin half-life in adults (d)
2	TEQ	fraction absorbed	0.6 - 0.8	f_ing: 0.70, Fraction of compound ingested that is actually absorbed (-). Adjusted downwards to reflect KTL sarcoma study concentrations
3	TEQ	fraction to child	0.05 - 0.1	f_mtoc: 0.075, Fraction of mother's compound burden that enters the child during breast-feeding in 6 mo. Alaluusua et Vartiainen used 0.25 but that produces way too high predictions (-)
4	TEQ	distribution volume in infant	5400	BF: 0.2 * 26.923 kg, body fat amount in 9-year-old boys
5	PFAS	half-life	1642.5 (912.5 - 3285)	t0.5: 4.5 (2.5 - 9) a * 365, PFOS half-life in adults (d), EFSA, slightly adjusted
6	PFAS	fraction absorbed	0.1 - 0.15	f_ing: 0.80, Fraction of compound ingested that is actually absorbed (-) See below.
7	PFAS	fraction to child	0.2 - 0.4	f_mtoc: 0.25, Fraction of mother's compound burden that enters the child during breast-feeding in 6 mo. Alaluusua et Vartiainen (-)
8	PFAS	distribution volume in infant	1580	BF: 200 ml/kg for PFOS * (7.692 kg + 8.141 kg) / 2, body fat amount in the infant at six months of age (g) [[:op_en:Body weight of 0-24 months old Finnish children]].
9	MeHg	half-life	1	t0.5: nominal
10	MeHg	fraction absorbed	1	f_ing: nominal
11	MeHg	fraction to child	1	f_mtoc: nominal
12	MeHg	distribution volume in infant	0.0714	BF: total conversion factor for mother's intake (ug/kg/d) to mother's hair (ug/g)

Dioxin kinetics

Previously we looked at the infant at six months of age, because that was arguably the age with peak dioxin concentration. The amount of breast milk consumed is likely to decrease and also the body dilution reduces concentrations. This would be a relevant time point for the dental aberration effect. However, EFSA considers the sperm concentration as the most sensitive endpoint of dioxins, and that ERF is based on dioxin concentration in 9-year-old boys. Therefore, we try to estimate dioxin concentration at the age of 9 years to be comparable to the EFSA ERFs.

Body weight data comes from Body weight of 0-24 months old Finnish children and Body weight of 2-18 year old Finnish children.

PFAS kinetics

ccording to EFSA, a long-term exposure of 4.4 ng/kg/d to PFAS leads to 6.9 ng/ml in blood. This implies that f_m = 6.9 ng/ml / 4.4 ng/kg/d / 1642 d * 200 ml/kg * ln2 = 13 % of PFAS is actually absorbed by the mother.

This in turn leads to PFAS concentration of 17.5 ng/ml blood in the child, i.e. ca 2.5-fold compared with the mother. This implies that FE = c_s,i / amount in mother * BF_i = 17.5 ng/ml / (6.9 ng/ml * 200 ml/kg * 70 kg) * (200 ml/kg * 8 kg) = 0.29.

Calculations

• Ovariables initiated 19.5.2017 [1]
• Updated 30.5.2017 [2]
• This code was called initiate with dx.expo.child until 13.6.2019. Now it has expo_indir for indirect exposure estimates. Indirect here means that the exposure is not directly estimated from environmental concentrations but indirectly from mother's exposure.
• An updated code expo_indir2 includes PFAS as well as dioxin. 2021-01-20 [3]

+ Show code- Hide code # This is code Op_en7797/expo_indir2 on page [[Infant's dioxin exposure]] library(OpasnetUtils) ################## CREATE a separate ovarible about children's exposure via mother's milk. # Convert mother's compound intake (pg/d) into child's compound concentration (pg/g) in fat after 6 months of breast-feeding. # For details, see [[ERF of dioxin#Dental defects]] and [[:op_fi:PFAS-yhdisteiden tautitaakka]] a <- opbase.data("Op_en7797", subset = "Parameters") # [[Infant's dioxin exposure]] t0.5 <- Ovariable("t0.5", data = a[a$Parameter == "half-life" , ][-c(1,3)]) f_ing <- Ovariable("f_ing", data = a[a$Parameter == "fraction absorbed" , ][-c(1,3)]) f_mtoc <- Ovariable("f_mtoc", data = a[a$Parameter == "fraction to child" , ][-c(1,3)]) BF <- Ovariable("BF", data = a[a$Parameter == "distribution volume in infant" , ][-c(1,3)]) expo_indir <- Ovariable( "expo_indir", dependencies = data.frame( Name = c( "expo_dir", # Mother's exposure to compound (pg/d) "t0.5", # Half-life of compound in mother (d) "f_ing", # Fraction of compound ingested by mother that is actually absorbed "f_mtoc", # Fraction of mother's compound body burden that enters the child during 6 mo breast feeding. "BF" # Distribution volume (ml) (or body fat amount (g) re dioxin) in the infant at 6 mo of age ) ), formula = function(...) { out <- expo_dir * f_ing * t0.5 / log(2) # Body burden in mother after long constant exposure out <- out * f_mtoc / BF # compound concentration in child (per g fat or ml blood) out$Exposure <- "To child" return(out) } ) objects.store(t0.5, f_ing, f_mtoc, BF, expo_indir) cat("Ovariables t0.5, f_ing, f_toc, BF, expo_indir stored.\n")

See also

• Human PBPK model for dioxin