The Toxicological Effects of Halogenated Naphthalenes: A Review of Aryl Hydrocarbon Receptor-Mediated (Dioxin-like) Relative Potency Factors

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The Toxicological Effects of HalogenatedNaphthalenes: A Review of ArylHydrocarbon Receptor-Mediated (Dioxin-like) Relative Potency FactorsJerzy Falandysza, Alwyn Fernandesb, Ewa Gregoraszczukc & MartinRoseb

a University of Gdańsk, Gdańsk, Polandb The Food and Environment Research Agency, York, Englandc Jagiellonian University, Kraków, PolandPublished online: 16 Sep 2014.

To cite this article: Jerzy Falandysz, Alwyn Fernandes, Ewa Gregoraszczuk & Martin Rose(2014) The Toxicological Effects of Halogenated Naphthalenes: A Review of Aryl HydrocarbonReceptor-Mediated (Dioxin-like) Relative Potency Factors, Journal of Environmental Science andHealth, Part C: Environmental Carcinogenesis and Ecotoxicology Reviews, 32:3, 239-272, DOI:10.1080/10590501.2014.938945

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Journal of Environmental Science and Health, Part C, 32:239–272, 2014Copyright C© Taylor & Francis Group, LLCISSN: 1059-0501 print / 1532-4095 onlineDOI: 10.1080/10590501.2014.938945

The Toxicological Effectsof Halogenated Naphthalenes:A Review of Aryl HydrocarbonReceptor-Mediated(Dioxin-like) Relative PotencyFactors

Jerzy Falandysz,1 Alwyn Fernandes,2 Ewa Gregoraszczuk,3

and Martin Rose2

1University of Gdansk, Gdansk, Poland2The Food and Environment Research Agency, York, England3Jagiellonian University, Krakow, Poland

There is no doubt that chloronaphthalenes (PCNs) and their brominated coun-terparts (PBNs) are dioxin-like compounds, but there is less evidence for mixedbromo/chloronaphthalenes (PXNs). In this article we review information relating to thedioxin-like potency of PCNs and PBNs obtained in vivo, in vitro, and in silico. The aimwas to help and improve the quality of data when assessing the contribution of thesecompounds in the risk analysis of dioxin-like contaminants in foods and other sampletypes. In vivo and in vitro studies have demonstrated that PCN/PBN congeners are in-ducers of aryl hydrocarbon hydroxylase, ethoxyresorufin O-deethylase, and luciferaseenzymes that are features specifically indicative of planar diaromatic halogenated hy-drocarbons such as dioxin and dioxin-like compounds. PCNs in the environment are ofmultisource origin. The limited data on PBNs in the environment suggest that thesealso appear to originate from different sources. The toxicological data on these com-pounds is even scarcer, most of it directed toward explaining the exposure risk fromaccidental contamination of feed with the commercial PBN containing product, Fire-master BP-6. The occurrence of PBNs and PXNs is possible as ultra-trace environ-mental and food-chain contaminants produced at least from combustion processes at

Address correspondence to Jerzy Falandysz, University of Gdansk, 63 Wita StwoszaSt., Gdansk 80-308, Poland. E-mail: [email protected] versions of one or more of the figures in the article can be found online atwww.tandfonline.com/lesc.

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240 J. Falandysz et al.

unknown concentrations. Available toxicological and environmental data enable a fo-cus on PCNs as dioxin analogues to an extent that specific local or regional environ-mental influences could result in a risk to human health. There is the possibility thatthey may act synergistically with the better-known classic dioxin and other dioxin-likecompounds. PBNs and PXNs are much less studied than the dioxins, but are known tobe products of anthropogenic processes that contaminate the environment. A continu-ously increasing use of bromine for manufacture of brominated flame retardants overthe past three decades is anticipated as a stream of “brominated” wastes, that whendegraded (combusted), will release PBNs and PXNs. This calls for advanced analyt-ical methods and greater interest toxicologically to understand and control pollutionand exposure by PBNs and PXNs. Particular congeners of bromonaphthalene in singlestudies were found to be much more toxic than their chlorinated counterparts. In addi-tion, brominated/chlorinated naphthalenes also seem to be more potent toxicants thanPCNs.

About 20% of PCN congeners exhibit a dioxin-like toxicity with relative poten-cies varying between around 0.003 and 0.000001, but additional and more rigor-ous data are needed to confirm these figures. Recent food surveys have estimated asmall but relevant human exposure to these compounds in foods, giving an additionalsource of dioxin-like toxicity to those compounds already covered by the World HealthOrganization–Toxic Equivalency Factors (TEFs) scheme. Given the additivity of re-sponse postulated for other dioxin-like compounds, it would seem unwise to ignore thisadditional contribution. Few data available showed that PBN congeners also exhibita dioxin-like toxicity and are even more potent than PCN congeners, but the relativepotency values were not derived for them until now. There are no toxicological dataavailable for PXNs.

Keywords: dioxin-like compounds; dioxin-like toxicity; persistent organic pollutants(POPs); polychlorinated naphthalenes; polybrominated naphthalenes; mixed bromi-nated/chlorinated naphthalenes

1. INTRODUCTION

Chloronaphthalenes (CNs; polychlorinated naphthalenes; PCNs) and theirbrominated counterparts (PBNs) are groups of 75 compounds each, and mixedhalogenated bromo/chloronaphthalenes (PXNs, or PB/CNs) are a group of 1550compounds (Figure 1, Table 1). PCNs, PBNs, and PXNs can be recognized asenvironmental pollutants, and current evidence shows that at least PCNs arefound in humans and other biota, food webs, air, soils, and surface water on a

Figure 1: Structure and ring numbering system of CNs. The positions 1, 4, 5, and 8 are calledα-positions (peri or apical positions). Positions 2, 3, 6, and 7 are β-positions or lateral positions.

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Dioxin-like Potency of Halogenated Naphthalenes 241

Table 1: Bromo- (PBNs), Bromo/Chloro- (PB/CNs or PXNs) and Chloro- (PCNs)Derivatives of Naphthalene-Homologue Groups and Number of Isomers and TotalNumber of Congeners

Substitution

Compound Mono Di Tri Tetra Penta Hexa Hepta Octa Total

PBNs 2 10 14 22 14 10 2 1 75PB/CNs//PXNs 0 14 84 254 420 452 252 0 1550PCNs 2 10 14 22 14 10 2 1 75

global scale [1], while there is much less information on sources of PBNs andPXNs, and this is discussed next. PCNs are physically and chemically stable,persistent, lipophilic, and the vast majority of congeners are known to undergobioaccumulation in biota [2]. In PBNs and PXNs, the Br C bond is relativelystronger than the Cl C bond, and the polarizability of Br C bond is greatercompared to Cl C bond in compounds.

All 75 polychlorinated naphthalene congeners are considered more or lessplanar compounds [3] and isosteromeric to 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD). The brominated and brominated/chlorinated counterparts are ex-pected to show similar properties, although structural distortion due to thehigher mass and size of bromine may influence the degree of planarity. Thestructural similarity of these molecules to the highly toxic TCDD moleculesuggests an aryl hydrocarbon (AhR)-mediated mechanism of toxicity, also com-monly referred to as dioxin-like toxicity. This mode of action has been con-firmed by a number of studies [4–9]. As was the case for some of the olderdioxin and PCB studies, the analytical purity of standards used for toxicitytesting is critical and was not always addressed by the authors. It is possiblethat PCN standards may be contaminated with dioxins or other compoundsthat in only small amounts may influence the impact of the toxicity of the com-pound under investigation.

The aim of this article is to discuss and update information on sources andtoxicity with focus on the dioxin-like potency of PCNs that is available frompublished tests done in vivo, in vitro, and in silico, while in practice little ornothing is known for PBNs and PXNs. This can help and improve the qualityof data when assessing the contribution of the risk analysis of total exposureto dioxin-like contaminants from foods, etc.

2. SOURCES

Large-scale production and unintentional formation as byproducts in other in-dustrial chemicals, followed by open-ended usage, has led to diffusion of PCNs

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into several environmental compartments: air, water, soil, biota, etc. As indus-trial chemicals with good dielectric properties they were the only halogenatednaphthalenes that were manufactured in large quantities—mostly between∼1910 and the ∼1970s in several countries, and were widely used [3, 10–12].They have also been reported as occurring as significant impurities in cer-tain chemicals (e.g., chlorobiphenyls; polychlorinated biphenyls; PCBs) [13].There is no information on natural (volcano eruptions, plant biomass fires,etc.) formation, but this can be anticipated at ultra-trace levels as the forma-tion of other similar chlorinated aromatic such as dioxins is widely known tooccur through this de novo synthesis pathway in thermal reactions like com-bustion. Today they have been identified as products of various combustionprocesses.

Analogous to chloronaphthalenes, bromonaphthalenes (largely penta- andhexa-) have also been identified as impurities in flame retardants, for example,in Firemaster BP-6 (or FF-1), which is a technical formulation of polybromi-nated biphenyls (PBBs) [14, 15]. Highly brominated biphenyl-based flame re-tardants were also manufactured, examples of which are octabromobiphenyl(Bromkal 80 was synthesized until 1985) and decabromobiphenyl (FlammexB-10 and Aldine until 1977 and 2000, respectively) [16]. There is no informa-tion available on the possible inadvertent occurrence of bromonaphthalenes inthese flame retardants. Data on occurrence of bromonaphthalenes in food andthe environment appear to a non-existent, but it has been reported that Fire-master BP-6 was mistakenly added to cattle feed resulting in contamination offoods in Michigan, USA in 1973 [14].

Bromonaphthalenes in trace quantities were also found among productsformed in the pyrolysis of brominated flame retardants [17]. Under laboratoryconditions, the lower molecular weight (mono- and di-) bromonaphthalenesand mixed bromochloronaphthalenes have been shown to be produced duringthe chlorination of water in the presence of naphthalene and potassium bro-mide [18], and from naphthalene adsorbed on fly ash and heated (50–250◦C)with hydrogen chloride and helium [19]. A few toxicological data exist on someindividual PBNs (see section on toxicity), but environmental data for PXNs arescarce, and no toxicological information is available. However, PXNs should beconsidered as also having dioxin-like activity.

By analogy to the mixed bromochlorobiphenyls (poly-brominated/chlorinated biphenyls; PXBs) [20], which have been detected in the environ-ment and in food [21], the occurrence of PXNs can be anticipated, as traceenvironmental contaminants formed unintentionally, during the combustionof materials containing brominated or chlorinated (or those containing bothbromine and chlorine) chemicals. An increasing use of long-lived brominatedflame retardants and ongoing disposal of their wastes probably becomes anincreasingly important source of PBNs and PXNs in the environment. This re-view is largely focused on PCNs that are environmentally and toxicologically

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the best characterized of the halogenated naphthalenes, but we do also con-sider the few toxicological data available on individual bromonaphthalenes.For human exposure, the most relevant source of PCNs is usually from thefood-chain as a result of environmental contamination.

3. ADVANCES IN ANALYSIS

A general issue when studying chloronaphthalenes in the context of elucidat-ing toxicological effects is, to a certain degree, the analytical challenges in com-plete speciation of the congeners. In some cases, this is primarily a chromato-graphic issue as “routine” analyses by mono-dimensional capillary gas chro-matography (GC) coupled with mass spectrometry (MS) has insufficient sepa-ration/resolution power. The main reason is the close co-elution of many toxico-logically and environmentally relevant congeners, which can occur even during“congener-specific” determination by capillary GC and high resolution MS andregardless of sophisticated procedures of their pre-separation (fractionation)before final instrumental measurement [22–24]. The correct recognition andidentification of compounds at the chromatogram stage is also essential(Figure 2). Another significant issue is the lack of commercially available ana-lytical standards for all 75 chloronaphthalenes or at least those that are toxico-logically relevant—native and isotopically labelled. In a few published studiesonly, and for selected matrices, was it possible to cover all CN homologousgroups—from monoCNs to octaCN, when using mono-dimensional capillarygas chromatography and high-resolution mass spectrometry. For the first time,the congener-specific carbon isotopic analysis of chloronaphthalenes usingtwo-dimensional gas chromatography-combustion furnace-isotope ratio massspectrometry (GCxGC-C-IRMS) was developed, which enabled improved res-olution and sensitivity of compound-specific carbon isotope analysis and thusthe study of chloronaphthalenes sources and fate [25]. Recently a method forthe complete separation and determination in one instrumental run andwithout any pre-separation or fractionation of analyte for all tetra-, penta-,and hexaCNs as well as heptaCNs and octaCN (together 49 compounds) in amixture has been reported [26]. This involved a set of two capillary columns ofdifferent polarity in two-dimensional GC and quadropole MS (GC × GC/QMS)(Figure 3). This method provides a highly advanced analytical tool for the fullresolution and improvements in risk assessment of all toxicologically relevantchloronaphthalene congeners that contaminate food and the environment.

4. ENVIRONMENTAL DIFFUSION AND EXPOSURE

Chloronaphthalenes form part of a larger group of biologically activehalogenated aromatic compounds of largely anthropogenic sources in the

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Figure 2: Monodimentional high resolution gas chromatography-massspectrometry/electron impact-selective ion registering (HRGC-MS/EI-SIR) chromatograms oftetraCNs in the breast muscles of adult and juvenile white-tailed sea eagles (details of thepeaks numbering are explained in Table 4) [23].

environment and in foods, to which humans are exposed. Like other con-taminants, the scenario of human exposure to particular chloronaphthalenesand their mixtures can vary depending on the source of exposure. When thegeneral population is considered, the primary exposure route is through thediet. The chloronaphthalenes composition at source can undergo considerablemodification during the transfer to dietary components. Therefore, direct en-vironmental deposition onto fruits and vegetables may show different pro-files (selective volatilization of the lighter congeners, photo-degradation). Thetransfer to aquatic biota and terrestrial food chains including animals raisedfor food is influenced by other mechanisms—for water-based biota, electron-enhanced molecular modification, hydrolysis, adsorption, etc.; for terrestrialfood chains soil—impact microorganisms, re-evaporation, soil-to-terrestrialbiota food chain, and animals—metabolism. In both cases, the final modifi-cations are effected by metabolism and uptake of the surviving congeners, butthe impacts are similar—selective removal of more labile congeners and theretention of certain congeners based on structure. Those particular PCNs arecongeners that have no vicinal carbon atom substituted with chlorine (NVC

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congeners), that is, have adjacent hydrogen—one or more pairs on vicinal car-bon atoms, as explained earlier [27]. For example, the NVC congeners domi-nate the profile of PCNs that occurs in fish [28–30] to a much greater extentthan the DVC congeners (with a pair of hydrogen on vicinal carbon atoms).Clearly, the effects will vary depending on the tissue and animal species andits oxidizing enzymes potential. So, for example, 1,2,3,4,6,7-HxCN (#66; NVCcongener) is persistent in rat liver and is retained to a much greater degreethan 1,2,3,5,6,7-HxCN (#67; NVC congener) [31, 32]. The muscle tissue meatand adipose fat of Yaks (which are herbivores) from the high mountain of theeastern Tibetan plateau in Wolong showed mainly penta- to octa-chlorinatedNVC and DVC congeners, but also several easier biodegradable TrCNs [33].Numerous TeCNs could be observed in tissues of juvenile White-tailed SeaEagles (Haliaeetus albicilla) (Figure 2) with few in adult birds where onlythe more resistant congeners of tetra-, penta-, hexa- and heptaCNs remained[23]. As mammalian species, human metabolic activity can be expected to fur-ther influence the final pattern of CN occurrence in these dietary componentsobserved in human tissue.

Figure 3: Chromatogram of tetra- to hexaCNs in Halowax equivalent mixture separated bycomprehensive two-dimensional gas chromatography (GC × GC) with the aid ofquadrupole mass spectrometry (QMS) using Rt-β DEXcst as the 1st and DB-WAX as the 2nddimension columns (details of the peaks numbering are explained in Table 4) [26].

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Thus, depending on route and extent of exposure, the composition ofchloronaphthalene source mixture, and metabolic capacity of animal species, aselection of the 75 PCNs can be considered. In some of the higher-order species,for example, lamb, only a few congeners persist compared to fish [2]. A firststep, however, to targeting toxicologically relevant congeners involves the ana-lytical chemistry of PCNs, and in particular the chromatographic resolution ofthe occurring compounds. Several chloronaphthalene congeners within eachhomologue group (e.g., from tetra- to hexa-CNs; potentially 49 compounds)are known to co-elute during separation, depending on the stationary phasetypes used in mono-dimensional capillary column gas chromatography. Thus,depending on the matrix or species, only a complete separation of all congenerscan give deeper insight into their persistency and fate in the body of vari-ous animals [26]. There is considerable evidence on environmental contami-nation with PCNs [34–37], and more recently data on food and food resourceshave also become available [21, 27, 33, 38, 39, 40; and many others]. Food oc-currence shows contamination with CNs of homologue groups from TrCNs toOCN, while members of all eight CN homologue groups are found in ambi-ent air and surface/ground water. Selected data are summarized in Table 2. Incomparison to the knowledge on contamination in foods and the environment,there is less information on occurrence and body burdens of PCNs in humantissues and fluids [27, 41, 42].

Due to the direct mass production and to the dioxin-like potency of manycongeners, PCNs could represent a major stream of dioxin-like compoundsof anthropogenic origin. The manufacture of major technical PCNs formula-tions ranged up to, or in excess of, 150,000 tonnes [1]. But there is no ac-curate inventory for all leading manufacturers of PCNs formulations, andsome countries were more or less minor producers, for example, Japan (WakoPCN) and Poland (Woskol PCN) [43]. Some others, for example, productionin the former Soviet Union, Spain, and China, could not be quantified atall. Nevertheless, the influence of past production has been declining. Thiscan be observed in the content of PCNs in milk collected between 1972 and1992 from mothers in the Stockholm region (without a specific source of ex-posure to PCNs), which has halved over a period of eight years, a likely re-flection of both, elimination and reducing environmental exposure [44]. Thetime-trend data on occurrence of PCNs in some Lake Ontario food chains inNorth America and in the Baltic Sea in Europe have shown a stepwise re-duction over the past three to four decades [29, 40]. A decline in bulk de-position of airborne PCNs has been observed in aquatic environment sedi-ments as recorded in sedimentary layers of cores at several regions of theworld but time-trend data varies for those sites [45, 46, 47]. Even in the lastdecade in the Baltic Sea, the PCNs concentration has been reported to have“leveled off” [40].

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Tab

le2:

Co

nc

en

tra

tion

so

fC

NH

om

olo

gu

eG

rou

ps

an

dTo

talC

Ns

inSe

lec

ted

Ma

teria

ls—W

orld

wid

eR

esu

lts(A

da

pte

dfr

om

the

Re

fere

nc

es

Cite

d,R

esp

ec

tive

ly)

Ma

teria

ls

Air;

Bac

kgro

un

d//

Urb

an

,In

du

stria

lAre

as,

Barc

elo

na

inSp

ain

,200

5(n

=1/

/3)

Air;

Gh

an

ain

Afr

ica

,M

ay–

July

2010

(n=

13)

Ve

ge

tab

les;

Ca

talo

nia

inSp

ain

,20

06(n

=4

)

Fish

&Se

afo

od

;C

ata

lon

iain

Spa

in,

2006

(n=

14)

He

rrin

g;

Sou

the

rnBa

ltic

Sea

,199

2(n

=1/

3)∗

He

rrin

g;

No

rth

ern

Balti

cSe

a,

1999

(n=

9/35

5)

Lake

Tro

ut;

Lake

On

tario

;N

.Am

eric

a,

1979

→20

04(n

=29

/c

a.1

30)

Yak

Me

at;

Wo

lon

gin

Tib

et-

Qin

gh

ai

Pla

tea

u,

2007

Hu

ma

nSe

rum

;So

uth

Kore

a,

2007

(n=

61)

CN

sfg

/m3

fg/m

3p

g/g

we

tw

tp

g/g

we

tw

tp

g/g

we

tw

tp

g/g

we

tw

tp

g/g

we

tw

t#p

g/g

we

tw

tp

g/g

lipid

∗∗

Mo

no

CN

s(2

)�22

0//1

20–2

70W

DW

DW

DW

DW

DW

DW

DW

DD

iCN

s(1

0)21

0//9

9–22

0W

DW

DW

DW

DW

DW

DW

DW

DTr

iCN

s(1

4)63

//31

–91

7.8–

26W

DW

DW

DW

DW

D3.

0W

DTe

tra

CN

s(2

2)24

//10

–37

12–7

61.

315

1200

12–3

143

0→

110

4.3

887

Pen

taC

Ns

(14)

2.4/

/1.7

–3.7

0.77

–5.3

0.5

2813

0038

–130

1400

→32

04.

837

8H

exa

CN

s(1

0)<

1.7/

/<1.

7–<

1.7

0.04

–1.2

0.2

313

021

–88

6000

→25

01.

720

2

He

pta

CN

s(2

)<

1.7/

/<

1.7

–<1.

70.

10–0

.97

0.3

0.3

134.

2–15

750

→11

1.3

326

Oc

taC

N(1

)<

1.7/

/<

1.7–

15<

0.01

–0.6

70.

10.

1W

D<

0.2–

1.3

23→

0.1

0.13

70

Tota

l(75

)52

0//2

90–6

2027

–69

2.3

4726

0075

–260

##

8900

→69

016

1863

Re

fere

nc

es

[51]

[52]

[53]

[53]

[34,

54]

[30]

[29]

[33]

[41]

� Nu

mb

ero

fp

oss

ible

isom

ers

an

dc

on

ge

ne

rs,r

esp

ec

tive

ly.

∗ Nu

mb

ero

fp

oo

led

sam

ple

s/n

um

be

rof

spe

cim

en

s.∗∗

Me

dia

nva

lue

s.W

D,W

itho

ut

da

ta.

# Da

taa

dju

ste

dto

we

tw

eig

ht.

##R

an

ge

of

me

dia

nva

lue

s.

247

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These temporal declining trends appear to be related more to a reduc-tion of emissions from manufactured legacy PCNs rather than to new forma-tion or “combustion” related PCNs. Congeners such as 1,2,3,6,7-PeCN (#54),1,2,3,6,8-PeCN (#55), 1,2,3-TrCN (#13), 2,3,6-TrCN (#26), 1,2,3,6-TeCN (#29),and 1,3,6,7-TeCN (#44) are either not observed or are highly minor con-stituents in sources related to technical PCN and PCB formulations (e.g.,Halowax, Aroclor, etc.), but they are among chloronaphthalenes generated dur-ing thermal reactions, for example, combustion [1, 26, 48, 49]. The contributionof these combustion-related congeners to total gas-phase PCNs in the atmo-sphere [50], and also in deposition to sediments [47], appears to be increasingand may present a more significant source in the future. These combustion-related compounds occurred in a proportion of 0.5% to 2.4% of the total PCNsin Scots pine needles from Poland and from 5.8% to 12.5% of the total PCNs inpine trees needles from Japan (Figure 4). These regional differences in the pro-portionality of occurrence probably reflect differences in the intensity of localsources.

5. BODY BURDENS: FATE AND EFFECTS

As a result of historical incidents of PCN exposure coupled with the advancesin measurement techniques as described earlier, there is more toxicity andtoxicokinetic data on technical PCNs formulations as a result of occupational

0,46

2,4

5,8

12

9

11

0,39

2,5

0

1,2

0,00

2,00

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6,00

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%

Pine needles,Poland

Pine needles,Japan*

High temperaturesources**

Coal/w oodcombustionsources***

PCB/PCNformularions****

min max

Figure 4: The relative content of combustion-related CNs (#13, 26, 29, 44, and 54) in Pinetree needles and in several CNs sources [55], adapted.

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outbreaks in human and accidentally poisoned animals than there is for in-dividual chloronaphthalenes. Additionally, experimental data from in vivo andin vitro studies using both technical formulations and mixtures synthesized ona laboratory scale also exists.

AbsorptionAbsorption of radio-labelled 1,2-DiCN (#3) given orally at 400 mg/kg body

mass to male Wistar rats was rapid, at up to one hour (greatest concentrationin blood at 1 hr) and gradually declined [56, 57]. It can also be deduced thatabsorption of the higher chlorinated compound from the gastrointestinal tractwas efficient, from a recent toxicokinetic study [58] with [14C] 1,2,3,5,6,7-HxCN(#67; purity 81%) given to male Wistar in a single dose of 0.3 mg (150 kBq) peranimal.

In another study, octaCN was administered at 5 g per day over 18 days to acow that nursed a 2-month-old calf. A reduced milk flow was noted from day 7and ceased at day 29, but the calf was allowed to nurse and in deficit receivedmilk (free of OCN) from the dairy herd. The calf autopsied on day 50 afterthe start of treatment showed moderate signs of poisoning, which suggestschloronaphthalene poisoning through absorption and the possible excretion ofOCN or its metabolites in the milk [59].

[14C] hexabromonaphthalene-1,2,3,4,6,7-HxBN (#66) and 1,2,3,6,7,8-HxBN (#70) given by single gavage at 0.42 and 4.2 μmol/kg bm (0.25 and2.5 μg/kg bm) to the male Fischer-344 rats was incompletely absorbed fromthe alimentary tract since half or more of the dose was excreted in feces within3 days [14].

DistributionLower chlorinated compounds (1,8-diCN (#9) 2,7-DiCN (#12) and the high-

est chlorinated—octaCN (#75) when administered by intraperitoneal (i.p.) in-jection at 1 mg each, separately to three male Jcl:ICR mice, accumulatedmainly in adipose tissue and the heart on the first day. The half-life of CN#12in liver was 0.33 day and in adipose tissue was 0.80 day, and except forheart and spleen exceeded that of CN#9 in all other tissues, with CN#75showing the longest half-life of 1.82 day in liver and 3.72 day in adiposetissue [60].

Radiolabelled 1,2-DiCN (#9) given in a single gavage to male Wistar ratswas found largely in the liver and intestines after 24 h, and by day seven,radioactivity at 0.05% of the total dose, was found only in the skin and adiposetissue [56].

Asplund and colleagues [31, 32] noted the selective retention of 1,2,3,4,6,7-HxCN (#66) and 1,2,3,5,6,7- HxCN (#67) in rat liver, just 24 h after dosage with

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technical PCN Halowax 1014 formulation, followed by the stepwise disappear-ance (metabolism) in 32 days, of tetra-, penta- and also heptaCNs and octaCNfrom this mixture, both in the liver and adipose tissue of female Sprague-Dawley rats.

1,2,3,4-TeCN (#27) and 1,2,3,4,5-PeCN (#49) given i.p. to male OutbredWist (Rattus) rats at 10 mg/kg bm (800 kBq/animal) showed a slow turnoverin the rat body and they were excreted largely with feces (40% of #49 in 24 hand 40% of #27 in 48 h, which increased to 70% and 65% respectively, by 120 h)[61].

[14C] 1,2,3,5,6,7- HxCN (#67; purity 81%) after single administration byper os (p.o.) and i.p. to male Wistar rats at 0.3 mg (150 kBq) per animal at 24 hlater was largely retained in the liver (32% for p.o. and 38% for i.p. route). Inthe adipose tissue, retention was observed to be around 30% at 120 h, for bothroutes [58].

[14C] hexabromonaphthalene—1,2,3,4,6,7-HxBN (#66) and 1,2,3,6,7,8-HxBN (#70) given by intra-venous injection at a single dose of 0.42 μmol/kgbm (250 μg/kg bm) to the male Fishcher-344 rats was redistributed to liver,skin, muscle tissues, and adipose tissue and by day 35 was 26.2% retained inliver and 4.5% in adipose tissue [14].

MetabolismLower chlorinated and brominated naphthalenes (having vicinal carbon

atoms substituted with hydrogen) can undergo metabolic transformationlargely by hydroxylation via arene oxide intermediates and by hydroxylation-dechlorination. For mono-CNs and di-CNs, the hydroxylated metabolites, bothphenolic and conjugated, seem to be major products of biotransformation. Inpractice no data are available for triCNs, but with increasing number of halo-gens, chloronaphthalenes are likely to behave like other similar compoundsand to show greater resistance to enzymatic oxidation.

Ruzo and colleagues [62] administered 1-MonoCN (#1) and 2-MonoCN (#2)to female Yorkshire pigs and identified 1-chloro-4-hydroxynaphthalene (fromCN#1) after 160 minutes, and 2-chloro-3-hydroxynaphthalene (for CN#2) after200 minutes, in the blood.

In another experiment from the study, Ruzo and associates [63] admin-istered a number of chloronaphthalenes and 1,4-diBN (#5) by arterial in-jection in a single dose to a female Yorkshire pig. The major metabolitesobserved in the urine were 1-monochloro-4-hydroxynaphthalene from 1-chloro-4-[2H]naphthalene (#1); 1,2-dichloro-4-hydroxynaphthalene from 1,2-DiCN(#3); 1,3-dichloro-4-hydroxynaphthalene from 1,4-DiCN (#5); 1,3-dibromo-4-hydroxynaphthalene and 1,4-dibromo-8-hydroxynaphthalene from 1,4-DiBN

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(#5); and 1,2,3,4-tetrachloro-5-hydroxynapthalene and 1,2,3,4-tetrachloro-6-hydroxynaphthalene from 1,2,3,4-TeCN (#27). No metabolite could be de-termined for 1,2,3,4,5,6-HxCN (#63) as there was insufficient material formeasurement.

1,2-DiCN (#3), 2,6-DiCN (#11), and 2,7-DiCN (#12) given orally (400 mg/kgbm) to male Wistar rats in a single dose were metabolized to the hy-droxyl derivatives and found in urine as the glucuronide conjugates of1,2-dichloro-5,6-dihydroxy-5,6-dihydronaphthalene for CN#3; 2,6-dichloro-3-hydroxynaphthalene, and 2-chloro-6-hydroxynaphthalene for CN#11. 2,7-DiCN (#12) in part was observed unchanged, and in part conjugated as 2-chloro-7-hydroxynaphthalene [57].

In a study on rabbits and Sprague-Dawley rats 2,6-DiCN (#11) givenin a single dose (300 mg/kg bm) was in portion metabolized to 2-chloro-6-hydroxynaphthalene and unidentified 2,6-dichloro-monohydroxynaphthalene.

For 1-MonoCN (#1) and undefined DiCN given in a single 1 g/kg bm doseto male albino rabbits, and TeCN, the phase II metabolites were found as con-jugated with glucuronic acid, mercapturic acid, and as ethereal sulphate. ForTeCNs (undefined mixture) in particular 45% of the administered dose was ac-counted for by these metabolites with 38% excreted as glucuronic acid, 3% asmercapturic acid, and 4% as ethereal sulphate, while no conjugate metaboliteswere observed in case of administered PeCNs (undefined mixture), HpCNs(undefined mixture), and OCN [64].

When Halowax 1031 was injected arterially (30 mg/kg bm) to pigs, theurine collected within five hours showed 1-chloro-4-hydroxynaphthalene andtrace amounts of dihydroxy compound, and 2-chloro-3-hydroxynaphthalene[65].

Chloronaphthalene congeners with a higher number of chlorine atoms(tetra- to hexaCNs) can also be partially transformed to methylthio and methylsulfoxide metabolites. They also form metabolites that are bound to macro-molecules of the liver, kidney, and lung and are non-extractable with non-polarsolvents [66, 67].

EliminationThe studies described show that when laboratory animals are dosed with

lower molecular weight chloronaphthalenes, that is, MonoCNs, some DiCNsand TeCN, the compounds undergo metabolism and are excreted largely asconjugated metabolites via the kidneys. This metabolic pathway declines insignificance as the number of chlorines attached to the naphthalene moietyincrease. For higher molecular masses, that is, the penta- hexa-, hepta-, andoctaCN, the kidneys are not a particularly relevant route of elimination.

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1-MonoCN (#1) and 2-monoCN (#2) administered to female Yorkshire pigswere eliminated with urine as 1-chloro-4-hydroxynaphthalene for CN#1 and2-chloro-3-hydroxynaphthalene for CN#2 [62].

Radiolabelled 1,2-DiCN (#3) was injected to the genital vein at 200 mg/kgbm to two rats with cannulated bile ducts. Urine and feces were the majorexcretion routes with around 64% removal within 48 hours. Excretion viabile was also studied with 65% being excreted by day 7 [56]. However, forother rats in the study, with 1,2-DiCN (#3) at 200 mg/kg bm and which didnot have bile duct cannula, 42% of dose was excreted unchanged in the fe-ces at 7 days. This indicated that in part, re-absorption from the intestineoccurred, but the urinary pathway showed 35% excretion (as a hydroxylatedmetabolite) [57].

In a study by Cornish and Block [68], 1-monoCN (#1) given to male albinorabbits in a single 1 g dose was excreted at 79% within 48 hours in the urine,and DiCNat 92% in that time.

[14C] 1,2,3,5,6,7- HxCN (#67; purity 81%, and containing also unidentifiedHxCNs as minor constituents) given to male Wistar rats intragastrically (p.o.)and also intraperitoneally in a single dose of 0.3 mg (150 kBq) per animalshowed a biphasic decline in plasma concentrations. The t1/2 for phase I wasaround 6 hours and for phase II 350 h. In the 120 h after dosage up to around51% (p.o.) and around 34% (i.p.) of CN#67 was excreted through the feces [58].

As discussed earlier, in cows, OCN appears to be excreted through the milk,either as the administered compound or its metabolites [59].

Birnbaum and colleagues [14] studied the disposition of a mixture (60:40)of [14C] hexabromonaphthalene—1,2,3,4,6,7-HxBN (#66) and 1,2,3,6,7,8-HxBN(#70; but not 2,3,4,5,6,7-HxBN, which is mistaken enumeration) in the maleFischer-344 rats. The results suggested that the half-lives would be shorterthan those of the chloro-analogs and that only BN#70 would persist in the liver.[14C] HxBN given intra-venous at a single dose of 0.42 μmol/kg bm (250 μg/kgbm) to rats was 24% metabolized and excreted via bile and feces (excreted inbile is excreted in feces largely without enterohepatic recirculation) by day 1,43.7% by day 3, 58.8% by day 10, and 62.5% by day 35, while less than 0.6%was via urine.

6. TOXICOLOGICAL CONSIDERATIONS

Technical PCNs formulations have been in use for several decades, and infor-mation on their toxicological effects has gradually emerged, often as a resultof the toxic and sometimes fatal episodes among occupationally exposed hu-mans and the accidental poisonings of cattle (X-disease). Chloracne and livernecrosis and skin hyperkeratosis were major reported symptoms, along withothers (edema, body mass loss, etc.), that were also observed in experimental

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studies with calves, ewes, hamsters, guinea pigs, chickens, turkey poults,rabbits, and mice and rats. These have been covered in earlier reviews [69,70, 71]. In addition, bromonaphthalenes cause chloracne and a severe chlo-racne in human accidentally exposed to them in organic synthesis laboratory[72].

The knowledge of compositional variations between particular batches oftechnical PCN Halowax formulations used in toxicological studies as well asof other toxic impurities in the mixtures was generally lacking or could not beachieved in the past. It is actually known that batches of particular HalowaxPCNs products vary in chloronaphthalene content and composition [26, 73,74]. This variation also extends to a given type of product (a similar degreeof chlorination) from different manufacturers [12]. To compound this lack ofcompositional uniformity, numerous isomers and congeners of chlorobiphenyl,including dl-PCBs as well as chlorinated furans, dioxins, chlorobenzenes, andchlorophenols were identified in all types of the technical PCNs Halowax for-mulations examined [75, 76, 77, 78, 79]. Hence, toxicological data on specifictechnical formulations will be limited by batch-to-batch variations that arisefrom the compositional variability, both in PCNs content as well as impuritycontent. As such, they are only covered briefly in this review, and toxicitydata for individual naphthalene compounds are discussed in more detail wherethese are available.

Long-term studies on the toxicity of small doses of technical PCNs formu-lations or other chloronaphthalene (laboratory scale synthesis) mixtures or in-dividual compounds are largely unknown. In one lifetime study, Halowax 1014was given per os by gelatin capsules at 0, 1.1, and 11.0 mg/kg bm/day to groupsof five ewes [80]. In the median dose group (11.0 mg/kg) it was calculated that117 mg/kg was required for lethality, which occurred between days 90 and 131.All were found to show liver damage.

In a maternal toxicity study assessing embryotoxic, fetotoxic, and terato-genic effects of chloronaphthalenes, a mixture of tetra- (54%), penta- (8%),hexa- (23%), and HpCNs (14%) on pregnant rats during organogenesis, Ki-lanowicz and colleagues (81), reported dose-related fetotoxic (reduced bodyweight and length of the fetus, extension of renal pelvis and lateral brain ven-tricles, signs of delayed ossification and retardation in development of internalorgans) and teratogenic effects (cleft palate and hydronephrosis), recorded atall dose levels (0.3–9.0 mg/kg bw administered during organogenesis), includ-ing those that were non-toxic to mothers. PCNs were concluded to be potentfetotoxic and teratogenic agents, producing similar effects to those of othertoxic dioxin-like compounds.

Kilanowicz and associates [82] also examined the impact of “hexaCN” (pu-rity > 94%, with CN#67 content at 81%) on neurobehavioral functions in maleWistar rats receiving intragastric in repeated doses for 28 days, at 0.3 and1.0 mg/kg bm daily. They found that the hexaCN mixture induced disorders

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of motivational processes manifested by a number of effects. These includedanorectic effect caused by aphagia and adipsia; significantly reduced motor ac-tivity (hypokinesia); impaired long-term memory and acquired passive avoid-ance reaction; reduced pain threshold and shortened duration of anxiety reac-tion after pain stimulus (sensory neglect). Some of these neurobehavioral ef-fects (impaired long-term memory, reduced pain threshold, and stress-inducedanalgesia) were observed at the 0.3 mg /kg bm dose, without any signs of overttoxicity. The study also found that chloronaphthalenes (#67; 1,2,3,5,6,7-HxCNat ∼82% and some other HxCNs at ∼10% and HpCN at 5.85%) given intragas-trically to rats at 1, 10, and 100 mg/kg bm, decreased body mass (measuredafter 7, 14, or 21 doses/days), and increased both the level of total cytochromeP-450 and the activity of CYP 1A [83]. In rats receiving two high doses an ev-ident dose- and time-dependent increase in malondialdehyde levels occurredand this finding correlated with decrease of glutathione (GSH) level in theliver. The same mixture of chloronaphthalenes in acute (a single doses of 100and 250 mg/kg bm) toxicity tests caused a very strong (dose-depended) induc-tion of CYP 1A (EROD) activity in the rat liver with the maximum (18–22-foldover control) occurring at 240 h after intoxication. Repeated administration(1 and 10 mg/kg bm) caused significant induction (12–13-fold at the lower, andup to 1570% after 28 doses at the higher exposure rate) of isoform CYP 1A inliver. The activities of ALT and SDH in serum were unchanged. The sub-acutetoxicity test using 1,3,5,8-TeCN (#43; >95% purity) did not show noticeableeffects (EROD in liver and ALT in serum) [84].

1,2,3,4,6,7-HexaCN (#67) given by gavage at a relatively low dose of1 μg/kg bm per day to pregnant Wistar rats accelerated the onset of sper-matogenesis in male offspring, and this was associated with a body burden of5.75 ± 2.81 μg/kg in the fat of the dams at weaning [85]. In a study by Hoothand associates [9] effects of 1,2,3,4,6,7-HxBN (#66) and 1,2,3,4,6,7-HxCN (#67)were observed in the liver (hepatocellular hypertrophy, fatty change, necrosis,and inflammation) and thymus (atrophy) and hypertrophy and thymic atrophy.OctaCN given in a single oral dose of 500 mg/kg bm to three rabbits causedtheir death within seven days [68].

2,3,6,7-TeBN (#48) was around 21-fold more lethal than 2,3,6,7-TeCN (#48)to guinea pigs and 30-day LD50 value for CN#48, BN#48 and TCDD wasgreater than 11.3, 0.547, and 0.006 μmol/kg bm, respectively, and this cor-responded to greater than 3000, 242, and 2 μg/kg bm [86].

A mixture at a ratio 60:40 of HxBNs (1,2,3,4,6,7-HxBN; #66) and1,2,3,6,7,8-HxBN (#70) (mistakenly reported as 2,3,4,5,6,7-HxBN) was foundto be a potent fetotoxic and teratogenic agent to C57BL/6N mice [87]. Preg-nant mice dosed with 0.5, 1.0, 2.5, 5.0, 7.5, and 10.0 mg hexaBNs/kg bm perday on gestation days 6 through 15, and scarified on gestation day 18, hadincreased liver-to-body mass ratios compared to control animals at all doses.The fetal mortality rate increased as exposure increased at doses 5.0, 7.5, and

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10 mg/kg bm daily, as did the incidence of teratogenic effects for all doses. Themost sensitive fetal abnormalities noted were kidney lesions (hydronephrosis),followed by a reduction in the size of thymus and spleen, cleft palate, edema,sternebral anomalies, and delayed cranial ossification [87]. HxBN can causecentrolobular accumulation of lipid in the liver of the rat [88].

7. IMPACTS ON ENZYMES IN VIVO AND IN VITRO

The induction of aryl hydrocarbon hydroxylase (AHH) and EROD and lu-ciferase enzymes is a short-term biological response that is indicative of astructurally diverse range of chemicals including PAHs, but is especially as-sociated with planar diaromatic halogenated hydrocarbons such as dioxin anddioxin-like compounds, where the response combined with a selective clean-upcan form the basis of a bioassay (CALUX). There is cumulative toxicologicalevidence that both technical PCNs formulations and many individual chloro-and bromonaphthalenes resemble the highly toxic dioxin-2,3,7,8-tetrachlorodibenzo-p-dioxin, in their biological action and effects on animals [5, 6, 9, 14,81, 83, 84, 89–101].

MixturesIn an early study, Ahotupa and Aitio [103] investigated enzyme induction

in rats exposed to Halowaxes (type 1031, 1000, 1001, 1099, 1013, 1014, and1051) administered by intraperitoneal injection at single doses of 10, 50, and100 mg/kg bm. At the highest dose, Halowax 1014 and Halowax 1051, highlyenhanced the induction of ethoxycoumarin deethylation, benzeno[a]pyrene hy-droxylation and glucuronidation of 4-methylumbelliferone and 2-aminophenol.The induction was found to be dose-dependent.

In a study by Cockerline and colleagues [91], the Halowaxes (1000, 1001,1013, 1014, 1051, and 1099) administered by intraperitoneal injection to im-mature male rats at 150 μmol/kg bm (low dose) and 600 μmol/kg bm (highdose) enhanced microsomal benzo[a]pyrene hydroxylase activity and hepaticcytochrome P-450. The effects were found to be dependent on the degree ofchlorination of the mixture. The Halowaxes 1000, 1001, and 1099 showed thephenobarbitone type of induction observed for some PCBs, while Halowaxes1013, 1014, and 1051 showed mixed-phenobarbitone and 3-methylcholantrene-induction [91].

In another study, Halowax 1014 administered in a single i.p. dose at20 mg/kg bm to adult male Sprague-Dawley rats, produced a long-lastingoxidative stress in the liver. It induced EROD leading to increased peroxi-dation of lipid, and decreased hepatic vitamin A and E content. In liver italso decreased catalase and superoxide dismutase activities, increased glucose

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6-phosphatase dehydrogenase and GSH-S-transferase activities and GSH-content, while GSH-peroxidase activity was unaffected [103].

A mixture of PCNs (54% of TeCNs, 8% of PeCNs, 23% of HxCNs, and 14%of HpCNs) was given intragastrically to rats for 7, 14, and 21 days in a dose10 mg/kg bm daily, to examine the impact on γ-aminobutyric acid (GABA)metabolism in brain regions with a high amount of GABAergic neurons(cerebellum, brain stem, and basal ganglia). The PCNs altered activity ofglutamate decarboxylase (GAD), GABA-aminotransferase (GABA-T), succinicsemialdehyde dehydrogenase (SDH), and succinate dehydrogenase (SSA-DH)in the selected brain areas, except GAD in basal ganglia. A correlationbetween CNs action and disturbance in GABA metabolism in rat brain wassuggested, while prolonged (21 days) intoxication increased SDH-mediatedactivation of citric acid cycle (TCA) [104]. The same CNs mixture as previouslynoted when given i.p. to male Wistar rats at high single doses of 230, 500, and1000 mg/kg bm caused a dose- and time-depended (24, 72, and 240 hrs afteradministration) loss of body mass (to about 30%) and highly increased levelof total cytochrome P-450 and activity of CYP 1A (EROD) in the liver. Dosesof 500 and 1000 mg/kg caused increased concentration of malondialdehyde asthe measure of lipid peroxidation (oxidative stress) in liver [95].

Three mixtures of PBNs containing 5.0, 5.3, and 5.6 bromines permolecule, respectively (“A” with TeBNs, PeBNs and HxBN #66; “B” with PeBN,HxBN #66 and unknown PBNs at 22.4%, and “C” with PeBNs, HxBN #66and unknown PBNs at 60%) given by intraperitoneal injection (in corn oil)to immature male Wistar rats (at 15 to 150 μmol per kg bm on days 1 and3) showed a high induction of cytochrome P-450 (P-448) monooxygenases(3-methylcholanthrene-type inducers). A dose of 30 μmol per kg bm causedmaximal induction of benzo[a]pyrene hydroxylase activity. However, Fire-Master BP-6, which is a commercial PBBs mixture, and PBNs impuritieswas much less potent [98]. The potency at which these PeBNs and HxBNsinduced aryl hydrocarbon hydroxylase in rats is considerably greater thanthat reported for 2,3,6,7-TeBN [105].

The potential endocrine disrupting potential of CNs, was recently inves-tigated by Gregoraszczuk and associates [106] by evaluating the effects ofa commercial mixture—Halowax 1051 on ovarian follicular testosterone (T)and estradiol (E2) secretion. They suggested a non-linear dose–response effectof Halowax 1051 on steroidogenesis and steroidogenic enzymes activity andprotein expression. It should be noted that octaCN (#75), which is a majorcomponent of Halowax 1051 [73], is a potent AHH inducer [92]. They furthersuggested that the toxicological effects of CNs in the ovary are similar to thosecaused by chlorinated biphenyls, -dibenzo-p-dioxins, and -dibenzofurans. Infollow-up work, stimulatory effects, similar to TCDD, on the proliferation ofMCF-7 breast cancer cells, were observed for lower chlorinated CN congeners(#34, 39, 42, 46) but not for higher chlorinated congeners (#52, 53, 54, 66, 67,70, 71, 73, 74) [E.G., unpublished].

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Individual CompoundsSeveral individual CN congeners were examined in vivo for possible

effects on key liver enzymes. OctaCN (CN#75 of 99.7% purity), when givenby intraperitoneal injection on days 1 and 3 to one-month-old immaturemale Wistar rats at doses of 15, 60, 150, and 600 μmol/kg bm, induceddose-dependent hepatic cytochrome P-450, benzeno[a]pyrene hydroxylase, and4-chlorobiphenyl hydroxylase activities [92]. OctaCN is an MC-type inducerand a 15-fold increased activity of benzene(a)pyrene hydroxylase and 1.3-foldof DMAP N-demethylase was observed compared to control rats that weredosed with corn oil. Additionally, compounds such as 1,2,3,4,5,6-HxCN (#63),1,2,3,4,5,6,7-HpCN (#73), and 1,2,3,4,5,6,8-HpCN (#74) dosed at 30, 100,and/or 150 μmol/kg bm (i.p. on days 1 and 3) induced several drug metaboliz-ing enzymes, that is, DMAP N-demethylase, benzo[a]pyrene hydroxylase, andEROD. Heptachloronaphthalene #74 was the most potent, and compoundssuch as 1,2,3,4-TeCN (#14), 2,7-DiCN (#12), 1,8-DiCN (#9), 1,5-DiCN (#6),2-MonoCN (#2), and 1-MonoCN (#1) were inactive as AHH inducers [5]. Thesetwo studies suggest that the higher chlorinated and consequently, highermolecular weight CN congeners, that is, OCN (#75), are more potent AHHactivity inducers than their less chlorinated counterparts.

Female Harlan Sprague-Dawley rats (approximately 49–55 days old atstudy start) were administered 0, 0.5, 1.5, 5.0, 50, and 500 μg/kg, separatelyof CN#66 and #67 in 12 repeated doses and with 0.001, 0.003, 0.010, 0.100,and 0.300 μg/kg of TCDD in corn oil:acetone (99:1) over two weeks (fivedays/week plus two consecutive dosages before necropsy). There were five ratsin each treatment group and ten rats in the control group. Body weights wererecorded weekly and observations were recorded daily. At study termination,rats were necropsied and tissues processed for microscopic examination. Liversamples were collected (five/group) for determination of cytochrome P450 CYP1A1 (EROD) and CYP 1A2 (A-4-H; acetanilide 4 hydroxylase). No animalsdied during the dosing period. All animals were clinically unremarkable withthe exception of one rat (dosed with CN#66 at 0.5 mg/kg), which showedreduced weight at study termination. In more detail, CN#66 (at ≥ 0.5 μg/kg)was depicting generally enlarged hepatocytes, scattered mixed inflammatorycells, and rare large fat vacuoles. CN#67 (at ≥ 50 μg/kg) additionally showedsignificantly more fat vacuoles. Both CN#66 and CN#67 produced body weight,thymic, and liver changes similar to TCDD exposure. P450 (EROD and A-H-4)induction was similar across compounds—response was maximized for all com-pounds. The shape of the dose-response curve for EROD induction was similarbetween compounds, but the ED50 was different between compounds [9, 93].

Hooth and colleagues [9, 94] also studied the effects of 1,2,3,4,6,7-HxCN(#66) and 1,2,3,5,6,7-HxCN (#67) on CYP1A1-dependent EROD and CYP1A2-dependent acetanilide 4-hydroxylase (A-4-H) activity, and thyroid hormone(T4, T3 and TSH) concentrations in blood, incidences, and average severities

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of selected non-neoplastic lesions (hepatocellular hypertrophy, thymic atrophy,ovarian atrophy, thrombosis and heart and major vessels—any site) and se-lected organ (liver, thymus) and organ-to-body weights at study termination.When administered by gavage to female Harlan Sprague-Daley (HSD) rats andFischer 344 (F344) rats at doses of 0, 10, 50, 100, and 200 μg/kg bm, for ap-proximately 14 weeks, CN#66 was five to six times more potent than CN#67in both rat strains based on EROD activity. Both CN#66 and #67 had similarED50 values for EROD activity in both rat strains. Although ED50 values forA-4-H activity were similar for CN#66 and #67 in each strain, ED50 valueswere lower in F344 rats. In the other parameters tested, CN#66 was found tobe more potent than CN#67 at decreasing the total T4 concentration in HSDand F344 rats, and the concentrations were lower in HSD females comparedto F344 females. CN#66 significantly decreased total T3 concentrations in thehigh-dose group of F344 rats but did not significantly reduce T3 concentrationsin HSD rats. CN#67 did not significantly decrease T3 concentrations in HSDor F344 rats. TSH concentrations were not significantly different from control,at any dose of both compounds. At equivalent doses, CN#66 showed greatertoxicity than CN#67 in both rat strains, for a number of the other parameterstested, including significant decreases in terminal body weight and in total T4

conditions; increased liver weights and decreased thymus weights; increasedincidents of hepatocellular hypertrophy (starting from dose 1.0 μg/kg bm forHSD rats; p ≤ 0.05), thymic atrophy, ovarian atrophy, and thrombosis [9, 94].

The EC values of TCDD and TCDF and selected bromonaphthalenes forinhibition of specific [3H]TCDD binding sites in rat liver cytosol and in vivotoxicity to Hartley strain guinea pig are summarized in Table 3. TeraBN, andPBNs of greater molecular weight bind specifically and with high affinity tothe Ah receptor in rat liver cytosol preparations [89]. 2,3,6,7-TeBN (#48) is a3-methylholantrene-type (MC) inducer of liver microsomal drug-metabolizingenzymes that in rats showed a 104-fold lower potency than TCDD [105].

In early development tests with the zebrafish (Danio rerio), both 1,2,3,4,6-pentaCN (#50) and 1,2,3,4,6,7-HxCN (#66) at 20 μg/L showed no effect on lor-dosis, kyphosis, disrupted axial body, tail defect, reduced heartbeat, and ab-normal hatching. Although weak at lower concentrations, the abnormalitiesbecame very pronounced at concentrations of 30 to 50 μg/L, with #66 showingthe greatest embryotoxicity [100].

Li and associates [101] investigated the impact of high purity individualchloronaphthalenes and commercial PCNs mixtures on the thyroid system ina yeast two-hybrid assay. They reported that compounds such as 1-MonoCN(#1), 2-MonoCN (#2), 1,4-DiCN (#5), and 1,2,3,4-TeCN (#27) had no agonistactivity but were antagonist to the recombinant human thyroid receptor (TR-β), and the 20% relative inhibitory (RIC-20), occurred at concentrations lessthan 9.3 × 10−3 g/L. The observed antagonism was dose-dependent and valueof RIC-20 was 5.82 × 10−3 g/L for #1; 9.13 × 10−3 g/L for #2; 3.04 × 10−3 g/L for

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Table 3: EC 50 Values of TCDD, TCDF, and Selected Bromonaphthalenes forInhibition of Specific [3H]TCDD Binding Sites in Rat Liver Cytosol [89] and in vivoToxicity to Hartley Strain Guinea Pig [86, 89, 90], Adapted

Single-dose LD50-30

Compound ID EC50 (M) (μg/kg) (μmol/kg)RelativeToxicity∗

RelativeBinding∗∗

2,3,7,8-TeCDD TCDD 1 × 10−10 WD 0.006 0.011 502,3,7,8-TeCDF TCDF 5.5 × 10−9 WD 0.023 0.042 27.52,3-DiBN #10 3.2 × 10−6 WD WD WD 0.0162,3,6,7-TeBN #48 2.0 × 10−8 242 0.55 1.00 1.002,3,6,7-TeCN #48 WD WD >11.3 >20.5 WD1,2,4,6,7-PeBN #60 5.0 × 10−8 200 0.39 0.70 2.501,2,3,4,6,7-HxBN #66 3.6 × 10−8 361 0.61 1.10 1.801,2,3,5,6,7-HxBN #67 1.5 × 10−8 >3610ψ >6.06 >11.02 0.75

WD, Without data.∗The LD 50–30 dose (guinea pig) in μmol/kg related to 2,3,6,7-TeBN (#48).∗∗The EC50 (M) data (second column) related to 2,3,6,7-TeBN (#48).ψRelates to the greatest dose tested with no appreciable toxicity observed.

#4, and 2.47 × 10−3 g/L for #27. No agonist or antagonist affect were observedfor OCN (#75) or the Halowaxes (1000, 1001, 1013, 1014, and 1099) tested atconcentrations up to 10−2 g/L [102].

8. TOXIC EQUIVALENCY

A key question regarding toxicological risk arising from the occurrence ofPCNs in foods and through environmental diffusion is the effects of AHHreceptor binding, which is a common mechanism of action shown by dioxin-like compounds such as 2,3,7,8-TCDD and its planar analogues. Substitutedwith bromine or chlorine at 2,3,7,8- positions, dibenzo-p-dioxins and furansand dl-PCBs have assigned values of Toxic Equivalency Factor (TEF) orRelative Potency Factor (RPF) that express compound toxicity relative to2,3,7,8-TCDD, which as the most potent has an assigned TEF value of 1[107].

Development of values of TEFs for dioxins and other compounds of similarnature requires the meta-analysis of a significant number of high-quality tox-icokinetic and mechanistic data on each compound considered. Both, in vitroand in vivo data can be extremely useful, even though the volume of the lat-ter are often limited. Additionally, RPF values developed in silico can be alsouseful for compounds with none, or limited, original in vivo or in vitro toxicitydata [108].

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Studies in vivoREPs have been proposed for CNs #66 and #67 (purity for both > 99.9%)

determined using dose response modeling [independent (ip) and common (cp)parameter models] of CYP1A1 and CYP1A2 (from in vivo data with femaleHarlan Sprague-Dawley rats) and of thymic atrophy [9, 94]. An estimate ofRPF for CN#66 (CYP1A1) is at 0.0017 (ip) and 0.0015 (cp), and (CYP1A2) at0.0041 (ip) and 0.0022 (cp); and of REP for CN#67 is at 0.00029 (ip) and 0.00036(cp) and at 0.00067 (ip) and 0.00032 (cp), and an estimate for thymic atrophyis 0.0072 for CN#66 and 0.00032 for CN#67 (cp) [9, 93, 94].

Studies in vitroThe REPs and efficacies (% of TCDDmax) of several CN congeners were

evaluated using in vitro cell-based bioassays [4, 7, 8, 109, 110], and resultsare collated in Table 4. Those bioassays are based on the aryl hydrocar-bon (Ah)-receptor activity, using micro-EROD (ethoxy-resorufin-O-deethylase)that utilizes a wild type rat liver cell line (rat liver H4IIEC3/T cells), andDR-CALUX (Dioxin-Receptor-Chemical Activated Luciferase gene expression)that consists of a genetically modified rat hepatoma H4IIE cell line that in-corporates the firefly luciferase gene coupled to dioxin-responsive elements(DREs) as a reporter gene. These REP values have been used to expresstoxic equivalencies of PCNs in biota and food, either using REPs from singlestudies [111, 112] or after rationalization of REPs from different studies[21, 39].

Studies in silicoA few in silico studies [113, 114, 115], have predicted REP values of in-

dividual CNs through quantitative structure-activity relationships computing,using the available EROD and luciferase activities of individual CNs from thein vitro tests referred to previously [4, 7, 8, 109, 110]. Data from one study [115]provided a complete set for all CN congeners. Those data but with exception ofa few congeners for which predicted values were marked as uncertain (includ-ing CN#75) are included in Table S1 (available in the Supplemental materialonline).

9. CONSOLIDATED REPs

This article collates relevant information from toxicological studies on PCNsand includes the relative potencies (REPs) data produced for these compounds

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Table 4: Reported Ranges of Combined in vivo and in vitro Relative Potencies(REPs) for Individual CNs [4, 7, 8, 9, 93, 109, 110]

PCN Congener ID In vitro In vivo

1-CN 1 < 6.4 × 10−6 – 1.7 × 10−5 WD2-CN 2 < 2.2 × 10−7 – 1.8 × 10−5 WD1,2-DiCN 3 < 2.9 × 10−7 WD1,3-DCN 4 WD WD1,4-DiCN 5 5.1 × 10−9∗

– 3.5 × 10−5 WD1,5-DiCN 6 < 6.6 × 10−7 – < 1.2 × 10−6 WD1,6-DiCN 7 WD WD1,7-DiCN 8 WD WD1,8-DiCN 9 < 1.7 × 10−6 – 1.5 × 10−5a WD2,3-DiCN 10 < 5.9 × 10−6 – 2.7 × 10−5 WD2,6-DiCN 11 WD WD2,7-DiCN 12 < 4.2 × 10−7 WD1,2,3-TrCN 13 < 2.0 × 10−6 – < 4.4 × 10−6 WD1,2,4-TrCN 14 WD WD1,2,5-TrCN 15 WD WD1,2,6-TrCN 16 WD WD1,2,7-TrCN 17 < 8.4 × 10−7 WD1,2,8-TrCN 18 WD WD1,3,5-TrCN 19 WD WD1,3,6-TrCN 20 WD WD1,3,7-TrCN 21 WD WD1,3,8-TrCN 22 WD WD1,4,5-TrCN 23 WD WD1,4,6-TrCN 24 WD WD1,6,7-TrCN 25 WD WD2,3,6-TrCN 26 WD WD1,2,3,4-TeCN 27 < 1.6 × 10−6 – < 2.3 × 10−6 WD1,2,3,5-TeCN 28 WD WD1,2,3,6-TeCN 29 WD WD1,2,3,7-TeCN 30 WD WD1,2,3,8-TeCN 31 WD WD1,2,4,5-TeCN 32 WD WD1,2,4,6-TeCN 33 WD WD1,2,4,7-TeCN 34 < 4.2 × 10−7 – < 6.9 × 10−7 WD1,2,4,8-TeCN 35 WD WD1,2,5,6-TeCN 36 < 4.1 × 10−7 WD1,2,5,7-TeCN 37 WD WD1,2,5,8-TeCN 38 WD WD1,2,6,7-TeCN 39 WD WD1,2,6,8-TeCN 40 1.6 × 10−5∗

WD1,2,7,8-TeCN 41 WD1,3,5,7-TeCN 42 < 1.9 × 10−6 – 7.5 × 10−6 WD1,3,5,8-TeCN 43 WD WD1,3,6,7-TeCN 44 WD WD1,3,6,8-TeCN 45 WD WD1,4,5,8-TeCN 46 WD WD1,4,6,7-TeCN 47 WD WD2,3,6,7-TeCN 48 4.1 × 10−5 WD1,2,3,4,5-PeCN 49 WD WD1,2,3,4,6-PeCN 50 4.3 × 10−5 – 6.8 × 10−5 WD

(Continued on next page)

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Table 4: Reported Ranges of Combined in vivo and in vitro Relative Potencies(REPs) for Individual CNs [4, 7, 8, 9, 93, 109, 110] (Continued)

PCN Congener ID In vitro In vivo

1,2,3,5,6-PeCN 51 WD WD1,2,3,5,7-PeCN 52 < 1.8 × 10−6 – 4.2 × 10−6 WD1,2,3,5,8-PeCN 53 < 1.2 × 10−6 – < 1.8 × 10−6 WD1,2,3,6,7-PeCN 54 9.2 × 10−5 – 0.00058 WD1,2,3,6,8-PeCN 55 WD WD1,2,3,7,8-PeCN 56 0.0000024 – 0.00049 WD1,2,4,5,6-PeCN 57 1.7 × 10−6 – 3.7 × 10−6 WD1,2,4,5,7-PeCN 58 WD WD1,2,4,5,8-PeCN 59 WD WD1,2,4,6,7-PeCN 60 < 4.2 × 10−7 – < 2.8 × 10−5 WD1,2,4,6,8-PeCN 61 < 4.2 × 10−7 WD1,2,4,7,8-PeCN 62 WD WD1,2,3,4,5,6-HxCN 63 0.002 WD1,2,3,4,5,7-HxCN 64 2 × 10−5 WD1,2,3,4,5,8-HxCN 65 WD WD1,2,3,4,6,7-HxCN 66 0.00054 – 0.0039 0.0015 –

0.00411,2,3,5,6,7-HxCN 67 0.00028 – 0.002 0.00029 –

0.000671,2,3,5,6,8-HxCN 68 0.00015 – 0.002 WD1,2,3,5,7,8-HxCN 69 0.0000064 – 0.002 WD1,2,3,6,7,8-HxCN 70 0.00059 – 0.0095 WD1,2,4,5,6,8-HxCN 71 < 1.1 × 10−6 WD1,2,4,5,7,8-HxCN 72 7.1 × 10−6 – 6.0 × 10−5 WD1,2,3,4,5,6,7-

HpCN73 0.00040 – 0.003 WD

1,2,3,4,5,6,8-HpCN

74 4.1 × 10−6 WD

1,2,3,4,5,6,7,8-OCN

75 < 4.3 × 10−6 – 1.0 × 10−5 WD

WD, Without data.

to date. The REPs derived in vivo that is available only for chloronaphtha-lene congeners #66 and #67 agrees well with most of in vitro and in sil-ico data derived for these compounds (Tables 4 and S1) (Table S1 is avail-able online in the supplemental material). Thus, the REP of 0.002 couldbe temporally assigned both to CN#66 and CN#67 as a reasonable approx-imation. As congener CN#70 appears to have a similar Ah receptor bind-ing strength as CN#66 and #67, its assigned REP of 0.003 seems adequate(Table 4). Hence, the chloronaphthalenes #66, #67, and #70 can be classi-fied as having an order of magnitude greater dioxin-like potency comparedto octachloro- and octabromo dibenzo-p-dioxin and -dibenzofuran [108]. Theyare also an order of magnitude more potent than two dioxin-like non-orthochloro- and bromobiphenyls that are substituted at positions 3,3′,4,4′- and3,4,4′,5- (i.e., chlorobiphenyls and bromobiphenyls #77 and #81, respectively)

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or all mono-ortho chloro- and bromobiphenyls. Chloronaphthalene #73 could beconsidered as the next most potent PCN congener (Table 4) with an assignedREP of 0.0006, followed by CN#68 (0.0005), CN#54 (0.0002), CN#69 (0.0001),and CN#63 (0.00002). CNs #55, #64, #71, and #75 show lower potency withREPs of 0.00001. For chloronaphthalene congener #56 and #62, the REP is0.000005 and for congeners: #57, #58, #59, #60, and #61, the value is 0.000001.For remaining chloronaphthalenes, the REP values are less than 0.000001(Table 4).

10. SUMMARY

Chloronaphthalenes originating through releases from older electrical equip-ment, as byproducts in industrial chemicals and from combustion processes,are known to be environmental contaminants. Recent advances in mea-surement techniques have allowed a greater speciation of PCNs occurrence,allowing the measurement of all 49 of higher molecular weight (from tetra-to octaCN) individual compounds. The toxicology of these contaminants re-veals a range of biological effects including enzyme induction, the most stud-ied of which are the AhR-mediated responses, often referred to as dioxin-liketoxicity.

The global volume of intentionally manufactured PCNs is estimated asca. 150,000 tonnes worldwide, and their “mass” dioxin-like impacts have, in asignificant measure, already occurred. There is little doubt that PCNs orig-inating from this source will continue to be seen as environmental pollu-tants, particularly as significant concentrations are still observed in environ-mental sinks, biota, and food. Concentrations, at least in some regions, aretemporally decreasing. Some quantities of PCNs are also produced and dif-fused into the environment through combustion processes. Combustion is alsoa probable environmental source of bromonaphthalenes and mixed bromo-/chloronaphthalenes, which can contribute to dioxin-like impacts by PCNs andrelated compounds.

The available evidence shows that some chloronaphthalenes exhibitdioxin-like potency but at a lower level, relative to 2,3,7,8-TCDD; others,mostly lower chlorinated congeners, can be considered to have little or no prac-tical dioxin-like relevance. The relevance of most potent PCNs (in the environ-ment and as food contaminants) can vary, depending on circumstances relatedto the type of source and extent of contamination and to biota (if not only hu-man) exposed. Hence, the determination and weighting of REPs may be rele-vant only for a few congeners. However, depending on circumstances such asthe concentrations determined, additional congeners (all 75 PCNs are more orless planar) may also contribute in part to the overall PCNs toxicity.

Data on individual congeners used in combination with REPs for relevantPCNs, at the moment currently provides a powerful tool for accurate weightingof their dioxin-like contributions and significance. Sufficient number of high

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purity standards for individual compounds could in future provide base forinsight into the AHH and other enzymatic inductions by all considered as tox-icologically and environmentally relevant PCNs, PBNs, and PXNs.

11. CONCLUSIONS

Chloronaphthalenes bind to the Ah receptor, but affinity is lower comparedto that of TCDD. The dioxin-like potency of 20% PCNs expressed by theREPs are between 0.003 and 0.000001. Chloronaphthalenes #66, #67, and #70with REPs between 0.003 and 0.002 are likely to be an order of magnitudemore potent compared to dl-tetraCB/tetraBBs and they are an order of mag-nitude more potent than octaCDD/F and octaBDD/F. Altogether 19 chloron-aphthalenes can be attributed as showing dioxin-like activity, while extra andmore rigorous data are necessary to confirm this conclusion. Some recent stud-ies have estimated a small but relevant contribution to dioxin-like toxicity infoods arising from these compounds. Given the additivity of response postu-lated for other dioxin-like compounds, it is important to consider this contribu-tion for risk assessments. Additionally, although a greater emphasis in this re-view has been placed on dioxin-like toxicity, other toxicological effects have alsobeen documented and it is important that these are also considered. Chloron-aphthalenes will continue to be relevant environmental and food-chain tracecontaminants because environmental exposure to PCNs (and probably less toPBNs and PXNs) by humans will continue in the future due to legacy andexisting sources of pollution.

SUPPLEMENTAL MATERIAL

Supplemental data for this article can be accessed on the publisher’s website.

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Documents

The Toxicological Effects of Halogenated Naphthalenes: A Review of Aryl Hydrocarbon Receptor-Mediated (Dioxin-like) Relative Potency Factors