Halogenated aromatic hydrocarbons and toxicity equivalency factors (TEFs) from the public health assessment perspective

Chemosphere,Vol. 31, No. 1, pp. 2547-2559, 1995 Pergamon 0045-6535(95)00123-9

HALOG~ATED FACTORS (TEFs)

Elsevier Science Ltd Printed in Great Britain

AR(JIATIC HYDROCARBOWS and TOXICITY EQUIVALENCY from the PUBLIC HEALTH ASSESSMenT PERSPECTIVE

H. Pohl and J. Holler Division of Toxicology Agency for Toxic Substances and Disease Registry Public Health Service U.S. Department of Health and Human Services Atlanta, Georgia 30333, U.S.A.

ABSTRACT

The validity of the toxicity equivalency factors (TEFS) approach to predicting toxicity of mixtures was investigated on the basis of the public health risk assessment that had been posted for different groups of halogenated aromatic hydrocarbons. First, the minimal risk levels (MRLs) were derived based on the databases available for chlorinated dibenzo-pdioxins (CDDs), chlorinated dibenzofurans (CDFs), and polychlorinated biphenyls (PCBs). The MRL values were then converted to 2,3,7,8tetrachlorinated dibenzo-p-dioxin (TCDD) toxicity equivalents (TEQs) and compared with each other. There was a good correlation between intermediate duration oral MRLs for TCDD and 2,3,4,7,8-pentaCDF when expressed in TEQs (7 pg/kg/day and 15 pg/kg/day). Although the studies that served for derivation of these MRLs used different species (guinea pigs and rats, respectively), the toxicity endpoints (inm~nological and hepatic for TCDD and hepatic for 2,3,4,7,8pentaCDF) were comparable. The hepatic effects were measured by the same techniques (blood chemistry and histopathology), ensuring similar sensitivity. However, there was a discrepancy between acute oral MRLs for TCDD and 2,3,4,7,8-pentaCDF when they were expressed in TEQS (20 pg/kg/day and 500 pg/kg/day, respectively). The studies used for MRL derivation involved not only different species (mice and guinea pigs, respectively), the immunotoxicity endpoints were measured by techniques with different sensitivity (serum complement activity versus histopathology), making comparison difficult. Further calculations showed that the TEFs approach may be feasible for individual coplanar congeners of PCBs, but not for a mixture of Aroclors. Correlations presented here support the concept that the TEFs are valid

2547

2548

only if specific criteria for their derivation are met (e.g., a broad database of information, consistency across endpoints, additivity for the effects, a common mechanism of action, etc.). In environmental exposure, the total toxicity of halogenated aromatic hydrocarbons is not necessarily the sum of the total individual congener toxicities because individual congeners compete for the same receptor; therefore, nonadditive behavior may occur.

INTRODUCTION

Halogenated aromatic hydrocarbons. to mixtures groups

of halogenated

are chlorinated

(CDFs),

and

contains

is

(CDDs),

biphenyls

congeners

(75,

The most

(PCBS).

135,

209

often

studied

chlorinated dibenzofurans Each

for

group

CDDS,

of

CDFS,

chemicals and

PCBs,

CDDs and CDFS, particularly, are closely related and occur in

the environment congener

People are environmentally exposed

hydrocarbons.

dibenzo-p-dioxins

polychlorinated

several

respectively).

aromatic

aromatic

together.

The most

2,3,7,8-tetrachloro

hydrocarbons

toxic

and

therefore

dibenzo-p-dioxin

that display properties

most

(TCDD).

studied

CDD

Halogenated

similar to those of TCDD are

called dioxin-like. Common

mechanism

of

toxicity.

proposed for dioxin-like chemicals to

steroid

hormone

A

common

(i, 2).

receptor-mediated

mechanism

of

toxicity

was

The process seems to be similar

response.

It

is

believed

that

halogenated aromatic hydrocarbons act by binding to an intracellular protein known as the Ah receptor.

Ah receptor activation is followed by its binding

to a translocating protein that carries the complex into the cell nucleus. The complex then interacts with a specific DNA sequence CYPIA1 gene,

which regulates

(the enhancer)

the expression of cytochrome

in the

P450IA isozymes,

changing the secondary and supersecondary structure.

The changes lead to an

increase in the CYPIA1 gene expression.

other yet unidentified

Furthermore,

genes may be involved in mediating the toxicity.

TEFs.

Concerns about health effects resulting from exposure to CDDS and

structurally

related

CDFs,

as well

as

the gaps

in present

knowledge

which to evaluate the human health risks associated with the exposure, been realized Chlorinated

(3, 4,

5, 6, 7).

The Environmental

Dibenzo-p-dioxins/Chlorinated

Protection Agency

Dibenzofurans

Technical

with have (EPA)

Panel

of

2549

the Risk A s s e s s m e n t

F o r u m r e c o m m e n d e d an i n t e r i m m e t h o d

risk a s s o c i a t e d

with

exposure

until

gaps

are

the

data

e q u i v a l e n c y factors

to

these

filled

(4,

chemical

8,

9).

This

toxicity

2,3,7,8-TCCD,

of

which

one

individual

is

halogenated aromatic unity,

that

method

the

can be u s e d

creates

toxicity

(TEFs) b a s e d on c o n g e n e r - s p e c i f i c data and the a s s u m p t i o n

that Ah r e c e p t o r - m e d i a t e d t o x i c i t y is additive. relative

for e s t i m a t i n g

mixtures

the

most

CDD

and

toxic

hydrocarbons.

and

The TEFs scheme compares the CDF

congeners

extensively

to

that

studied

The TEF for 2 , 3 , 7 , 8 - T C D D

of

of

these

is d e f i n e d as

w h e r e a s TEF v a l u e s for all other CDD and CDF c o n g e n e r s are less than

(zero has b e e n a s s i g n e d to all n o n - 2 , 3 , 7 , 8 - s u b s t i t u t e d

reflecting

the

g e n e r a t e d TEFs estimating

lower

toxic

potency

can be used,

the

toxicity

of

most

CDD

and

congeners),

CDF

thus

congeners.

The

a s s u m i n g a d d i t i v i t y of the toxic response,

of

an

environmental

mixture

containing

a

for

known

d i s t r i b u t i o n of CDDs a n d / o r CDFs r e l a t i v e to t o x i c i t y of 2,3,7,8-TCDD.

The

interim TEF v a l u e s will change over time as new t o x i c i t y data are obtained. The TEF a p p r o a c h aids in s i t e - s p e c i f i c a s s e s s m e n t s of risks a s s o c i a t e d with exposure

The

to m i x t u r e s of d i o x i n - l i k e chemicals.

usefulness

Assessment Forum the

coplanar

recommended further

of

TEFs

(8, 10).

PCB using

testing

for

congeners TEFs of

PCBs

was

also

debated

before

EPA'S

Risk

A t t e m p t s have b e e n m a d e to a s s i g n TEFS to some of

for

and PCBs

individual

Aroclor as

an

mixtures. interim

congeners

However,

procedure

and

mixtures

the

and

Forum

encouraged

found

in

the

environment.

METHODS

MRLs.

ATSDR

develops

toxicological

profiles

for

chemicals

h a z a r d o u s w a s t e sites i n c l u d e d on the N a t i o n a l P r i o r i t i e s List. include

all

literature. expressed

chemical-specific Risk

as

the

associated minimal

risk

toxicologic with

exposure

level

data to

(MRL).

from a

By

found

at

The p r o f i l e s

the

scientific

specific

chemical

definition,

"MRLs

is are

estimates of d a i l y h u m a n e x p o s u r e to a chemical that are likely to be without an

appreciable

risk

d u r a t i o n of exposure"

of

adverse (ii).

noncancer

health

MRLs are A T S D R ' S

effects

over

specific values

a

specified

that p r o v i d e

2550 health

professionals

health

effects

are

with not

working near h a z a r d o u s

estimates

expected

of

to

exposure

occur

in

levels

human

waste sites or chemical

at

which

populations

emissions.

adverse

living

or

MRLs are derived

from the most sensitive endpoint for the exposure period, w h i c h may be either the highest n o - o b s e r v e d - a d v e r s e - e f f e c t adverse-effect

level'

(LOAEL).

Human

level

(NOAEL) or the lowest-observed-

data

are

preferred;

equivalent

levels can be d e r i v e d b a s e d on animal exposures.

derivation

of an oral exposure MRL is: MRL = NOAEL

however,

human

The formula for

(or LOAEL)

(UF x MF) MRL =

minimal

risk level

(mg/kg/day)

NOAEL = n o - o b s e r v e d - a d v e r s e - e f f e c t

level

LOAEL = l o w e s t - o b s e r v e d - a d v e r s e - e f f e c t UF = u n c e r t a i n t y MF = m o d i f y i n g

factor

factor

MRLS p r e s e n t e d Profile

for PCBs

is the basis

this

(I).

document

reassessment

in this p a p e r are from the Toxicological (2)

The T o x i c o l o g i c a l

will

(mg/kg/day)

(unitles

for c o m p a r i s o n

Selected

level

(unitless)

Chlorodibenzofurans

updated,

(mg/kg/day)

and

the

Profile

Toxicological for CDDs,

for p r o p o s e d MRLs on TCDD be

of dioxin.

completed

pending

the

(12).

which

Profile

for

is now being

The final v e r s i o n of

formal

release

of

EPA's

The MRLs for TCDD have not yet been made final and

are not to be v i e w e d as current A T S D R p o l i c y on dioxins. TEQS.

The toxicity e q u i v a l e n t s

(TEQs) of TCDD were c a l c u l a t e d b y m u l t i p l y i n g

the MRLs by TEFs for 2 , 3 , 4 , 7 , 8 - p e n t a C D F and Lubet et al.

and A r o c l o r 1254 p r o v i d e d by EPA

(4)

(13). RESULTS and DISCUSSION

We

presume

mechanism

of

endpoints

should

that

action, be

because their similar.

dioxin-like toxicity

chemicals

outcomes

Therefore,

the

and

act

through

their

estimates

most of

a

common

sensitive

daily

human

exposure to specific congeners of d i o x i n - l i k e chemicals that are likely to be

2551

without

risks

similar

when

of

adverse

adjusting

specific congener

noncancer

for

the

health

relative

effects

potency

in

(MRLs) the

should

toxicity

also of

be

each

(TEQ).

The MRLS were d e r i v e d b a s e d on the d a t a b a s e s of the s p e c i f i c

group of

chemicals as d e s c r i b e d in the m e t h o d s section. The MRLs and their r e s p e c t i v e TEQ values are d i s p l a y e d in Table i.

Table

Chemical

TEF

1.

MRL

TEQ

(in pg/kg/day) TCDD (proposed)

1

acute intermed chronic

PentaCDF

0.5

acute intermed

Aroclor

3.4xI04

chronic

(in pg/kg/day)

20 7 0.7

20 7 0.7

1,000 30

500 15

20,000

0.07

Footnote: MRL = M i n i m a l R i s k Level TEFs = T o x i c i t y E q u i v a l e n c y Factors TEQs = T o x i c i t y E q u i v a l e n t s TCDD = 2 , 3 , 7 , 8 - t e t r a c h l o r o d i b e n z o - p - d i o x i n pentaCDF = 2,3,4,7,8-pentachlorinated dibenzofuran A r o c l o r = A r o c l o r 1254 - a c o m m e r c i a l m i x t u r e of p o l y c h l o r i n a t e d b i p h e n y l s acute = acute d u r a t i o n e x p o s u r e (14 days or less) i n t e r m e d = i n t e r m e d i a t e d u r a t i o n e x p o s u r e (15 to 364 days) chronic = chronic d u r a t i o n e x p o s u r e (365 days or more)

MRLS

and TEQs.

intermediate

As

duration

is s h o w n values

in Table for

T C D D / k g / d a y and 15 pg TEQs/kg/day, oral M R L of decreased

7 p g / k g / d a y was b a s e d

thymus

weight

in g u i n e a

TCDD

I, a good c o r r e l a t i o n and

2,3,4,7,8-pentaCDF

respectively). on a N O A E L pigs

is seen in (7

of 0.0007 ~ g / k g / d a y TCDD

exposed

pg

The i n t e r m e d i a t e d u r a t i o n

in their

feed

for

for

90 days

2552

(14).

From

~g/kg/day

this

TCDD)

reported

study,

was

at

immunological be

of

one the

for

levels This

for MRL same

# g / k g / d a y was b a s e d

supporting

identified

higher

hypertriglyceridemia.

would

a

NOAEL

liver

were

value.

on a L O A E L

The

same

value

(0.0007

The

liver

effects

toxicity.

would and

have

intermediate

as

based

valid

on

duration

effects

(15, 16).

inclusions

been

the MRL

for h e p a t i c

weeks to 2 , 3 , 4 , 7 , 8 - p e n t a C D F in feed

the

hepatocellular

endpoint

derivation,

of

this

MRL

in rats

and

as

the

endpoint

of

0.00003

exposed

for 13

The o b s e r v e d effects i n c l u d e d

i n c r e a s e d s e r u m b i l i r u b i n and d e c r e a s e d s e r u m t r i g l y c e r i d e s .

Liver was found

to be a target organ of t o x i c i t y for b o t h CDDs and CDFS.

High

discrepancy

2,3,4,7,8-pentaCDF

was

found

between

(20 p g T C D D / k g / d a y

and

acute

oral

MRLs

for

500 p g T E Q s / k g / d a y ,

TCDD

and

respectively).

The acute oral MRL of 20 p g / k g / d a y was b a s e d on the LOAEL of 0.01 ~ g / k g / d a y TCDD that i n d u c e d s u p p r e s s e d s e r u m c o m p l e m e n t a c t i v i t y in B 6 C 3 F I m i c e e x p o s e d to 14 d a i l y doses a d m i n i s t e r e d by g a v a g e in oil v e h i c l e MRL

for

2,3,4,7,8-pentaCDF

hypoplasia oil

was

based

on a L O A E L

(17).

for m i l d

The acute oral thymic

lymphoid

i d e n t i f i e d in g u i n e a pigs f o l l o w i n g a single g a v a g e dose in corn

(18).

The 2 5 - f o l d d i f f e r e n c e can be a t t r i b u t e d to the q u a l i t y of the d a t a b a s e of each group of c h e m i c a l s and to the s e n s i t i v i t y of tests for M R L derivation. •e x p o s u r e

study

immunological

in studies u s e d

H i s t o l o g i c e x a m i n a t i o n u s e d in the 2 , 3 , 4 , 7 , 8 - p e n t a C D F

cannot

detect

testing employed

subtle

changes

that

could

in the T C D D study.

discovered

by

A further d i f f e r e n c e

be

is

e x p o s u r e to a single dose of CDF c o m p a r e d w i t h 14 d a i l y doses of TCDD. are d i f f e r e n c e s

in the t o x i c o k i n e t i c s

There

of 2 , 3 , 7 , 8 - s u b s t i t u t e d CDDs and CDFS.

T o x i c o k i n e t i c studies r e v e a l e d that the e l i m i n a t i o n of CDD and CDF congeners is not only c o n g e n e r s p e c i f i c half-life in m o n k e y s

(for 2,3,7,8-TCDD)

(19, 20,

21),

(23) to 5.8 years in h u m a n s

(20).

doses may p l a y a role in final toxicity. were not c o n s i d e r e d w h e n TEF v a l u e s

Furthermore,

the

intermediate-duration

but also species

ranges f r o m 17 days in rats

TEFs in v i v o

are

specific;

the

(22) to about 1 y e a r

This m e a n s that a c c u m u l a t i o n of

However,

the t o x i c o k i n e t i c issues

for most c o n g e n e r s were derived.

either

studies

or

derived from

from

in v i t r o

short-term

experiments.

or In a

2553

recent study,

hepatic,

skin, and lung 7-ethoxyresorufin O-deethylase

(EROD)

and hepatic acetanilide-4-hydroxylase activities were determined in mice that were

fed

presumed

2,3,7,8-tetraCDF,

equipotent

doses

1,2,3,7,8-pentaCDF,

several PCB congeners for 4 weeks not

produce

chemicals,

equivalent indicating

(based

(24).

induction

on

published

1,2,3,4,6,7,8,9-octa

of

CDF,

TEFS)

of

TCDD,

and

The study showed that the doses did enzyme

activity

for

many

of

these

that the TEFs do not reliably predict potency at the

enzyme level. A chronic oral MRL of 0.7 pg/kg/day mild learning and behavioral

for TCDD was based on a LOAEL for

impairment in the offspring of monkeys exposed

to 0.0002 ~g/kg/day TCDD in feed

(25).

Sufficient

for derivation of a chronic oral MRL for CDFS. was derived for PCBs based on Aroclor 1254. pgTEQ/kg/day)

was

based

exposed to Aroclor

on

a

LOAEL

for

data were n o t

However,

available

a chronic oral MRL

The MNL of 0.02 ~g/kg/day

immunological

1254 in feed for 23 months

effects

(26, 27, 28).

10.07

in monkeys

Immunological

testing of exposed monkeys revealed decreased IgG and IgM levels in response to sheep red blood cells. Although the species used in both studies were the same, the end-points are different and would be difficult to compare.

The TEF value used for our

calculation is the one proposed by Lubet et al.

(13) based on immunological

endpoints.

When comparing TCDD toxicity with that of Aroclor 1254, we should

keep in mind that Aroclor

1254 is a mixture of PCBs.

Some of the PCBs are

coplanar and have a dioxin-like mechanism of action and similar toxicity endpoints.

However,

noncoplanar PCBs in the mixture are likely to act through

a different mechanism of action and influence final toxicity outcomes. Valldatlon

of

the

TEF

system.

Concurrent

exposure

to

mixtures

halogenated aromatic hydrocarbons is common in the general environment. TEF

system

was

developed

to

estimate

the

health

risks

exposure to mixtures of halogenated aromatic hydrocarbons. approach

is

controversial

because

it

is

only

useful

33).

To validate

interactions

between

the system, congeners

it is important

play

a

role

in

the

The

associated

with

However, the TEFS for

exhibit dioxin-like activity and is not adequately validated 32,

of

congeners

to know whether final

that

(24, 29, 30, 31, expression

or not of

a

2554

particular mixture's toxicity.

Because the TEFS approach to risk assessment

assumes additivity of toxic responses,

studies of the interactions of CDDS,

CDFS, and PCBs tried to determine possible changes in the relative potency of individual The

congeners

TEFs

in the presence of other congeners

approach

for assessing

mixtures

introduced for environmental exposure usefulness

of the TEFs approach,

feeding studies in rats.

(30).

(mostly TCDD).

of CDDS

and CDFs was

first

Additive effects, as well as the

was demonstrated

in intermediate-duration

Exposure to a mixture of TCDD, 1,2,3,7,8-pentaCDF,

and 1,2,3,6,7,8-hexaCDF showed additivity for hepatic and thymic effects

(16,

34). Additivity

was

also

seen

in

the

incidence

offspring of mice given a subcutaneous injection TCDD

and

2,3,7,8-tetraCDF

2,3,4,7,8-pentaCDF

and

during

palate

and

hydronephrosis)

had

when

cleft

palates

in

the

(35) or an oral dose (36) of

gestation.

1,2,3,4,7,8-hexaCDF

2,3,4,5,3',4'-hexachlorobiphenyl

of

Similarly,

and

of

additive

of

2,3,4,7,8-pentaCDF

teratogenic

administered

mixtures

orally

effects

to

and

(cleft

pregnant

mice

(37) .

In

contrast,

some

studies

demonstrated

tetraCDF are partial TCDD antagonists. the formation of splenic plaque-forming cells

in

mice

antagonistic

exposed

that

receptor

2,4,6,8-

cells as a response

1,3,6,8-tetraCDF

results were reported

and 2,3,4,7,8-pentaCDF. showing

to

that

and

TCDD

has

1,3 6,8-

to sheep blood (38).

Similar

for the combination of 1,3,6,8-tetraCDF

These results agree with previously

1,3,6,8-tetraCDF

and

The antagonistic effect was seen in

a

high

of

TCDD

affinity

for

the

released data cytosolic

Ah

(39).

Intraperitoneal inhibited

aryl

O-deethylase induction antagonist

(EROD)

caused

application

hydrocarbon by

activity

hydroxylase

induction exposure of

as to

and

compared TCDD

to

alone

1,3,6,8-tetraCDF

1,3,6,8-tetraCDF

(AHH)

was

and results

(40).

to

mice

7-ethoxy-resorufin The

dependent

of

AHH

maximum on

the

and

EROD

partial relative

concentration ratios of agonist and antagonist and was different for DBA/2J and C57BL/6J strains

of mice.

This important

result may have implications

2555

for environmental

exposure.

have a protective

role against the more toxic congeners.

As

is

the

case

The more abundant and less toxic congeners may

with

interactions

of

dioxins

administration of 2,2',4,4",5,5'-hexachlorobiphenyl resulted

in

antagonism

immunotoxicity

of

TCDD-mediated

and

furans,

co-

or Aroclor 1254 with TCDD

teratogenicity

(41,

42)

and

(43) in mice.

Some of the criteria for using the TEFs approach include a well-defined group

of

chemicals,

endpoints0 However,

a broad

database

additivity of the effects,

of

information,

all of these criteria are not met.

information congeners

to

derive

TEFS

for

consistency

across

and a common mechanism of action

each

(8).

Even if we could collect enough

congener,

the

final

behavior

of

all

in the particular mixture is not certain.

REFER~WCES

I.

ATSDR.

1992a.

biphenyls. Service, 2.

U.S.

Toxicological

Department

of

profile

Health

ATSDR.

1993.

Toxicological

profile

of Health and Human Services,

Toxic Substances and Disease Registry, Ahlborg

UG,

Brouwer

A,

environmental

health,

with

equivalency factor concept. EPA.

Human

Services,

Interim

MA,

emphasis

Eur J Pharmacol

U.S.

Agency for

GA.

et on

al.

1992.

Impact

of

and biphenyls on human and application

of

the

toxic

228:179-199. associated

with (CDDs

and 1989 update.

Environmental

procedures

Health GA.

chlorodibenzofurans.

dibenzofurans,

special

Public

Atlanta,

exposure to mixtures of chlorinated dibenzo-p-dioxins and dibenzofurans and CDFs)

1989.

for

polychlorinated

Public Health Service,

Atlanta,

Fingerhut

polychlorinated dibenzo°p-dioxins,

4.

selected

Agency for Toxic Substances and Disease Registry,

Department

3.

and

for

for estimating

Risk Assessment

Protection Agency.

Forum.

EPA 625/3-89/016.

risks

Washington,

DC:

NTIS PB90-145756.

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