Skin diseases associated with Agent Orange and other organochlorine exposures

REVIEW

Skin diseases associated with Agent Orange and other organochlorine exposures Andrew T. Patterson, MD,a,b Benjamin H. Kaffenberger, MD,a Richard A. Keller, MD,c and Dirk M. Elston, MDd,e Columbus, Ohio, and San Antonio, Texas Organochlorine exposure is an important cause of cutaneous and systemic toxicity. Exposure has been associated with industrial accidents, intentional poisoning, and the use of defoliants, such as Agent Orange in the Vietnam War. Although long-term health effects are systematically reviewed by the Institute of Medicine, skin diseases are not comprehensively assessed. This represents an important practice gap as patients can present with cutaneous findings. This article provides a systematic review of the cutaneous manifestations of known mass organochlorine exposures in military and industrial settings with the goal of providing clinically useful recommendations for dermatologists seeing patients inquiring about organochlorine effects. Patients with a new diagnosis of chloracne, porphyria cutanea tarda, cutaneous lymphomas (non-Hodgkin lymphoma), and soft-tissue sarcomas including dermatofibrosarcoma protuberans and leiomyosarcomas should be screened for a history of Vietnam service or industrial exposure. Inconclusive evidence exists for an increased risk of other skin diseases in Vietnam veterans exposed to Agent Orange including benign fatty tumors, melanomas, nonmelanoma skin cancers, milia, eczema, dyschromias, disturbance of skin sensation, and rashes not otherwise specified. Affected veterans should be informed of the uncertain data in those cases. Referral to Department of Veterans Affairs for disability assessment is indicated for conditions with established associations. ( J Am Acad Dermatol http:// dx.doi.org/10.1016/j.jaad.2015.05.006.) Key words: Agent Orange; chloracne; dioxin exposure; organochlorine; skin disease; veteran; Vietnam; 2,3,7,8-tetrachlorodibenzo-p-dioxin.

D

ermatologic ailments were the most common reason for outpatient visits to US Army medical facilities during the Vietnam War and the major cause of field days lost.1 Although immersion foot and zoonotic tinea comprised much of the acute dermatologic morbidity, long-term effects can often relate to organochlorine exposure. During the war, herbicides were used to defoliate enemy crops and cover in a campaign designated Operation Ranch Hand (ORH), lasting from 1962 to 1971. It exposed millions of soldiers and civilians to organochlorine chemicals, predominantly Agent

From the Division of Dermatology, Ohio State University College of Medicinea; US Air Force, San Antonio Military Medical Centerb; Dermatology, Audie L. Murphy Veterans Hospital, San Antonio, US Air Forcec; Ackerman Academy of Dermatopathologyd; and US Army (Retired).e Funding sources: None. Disclosure: Dr Keller is a full-time employee of the US Department of Veterans Affairs. Dr Patterson is employed as an active duty member of the US Air Force. Drs Kaffenberger and Elston have no conflicts of interest to declare. The contents of this article represent the authors’ views and opinions, but do not represent the views or policy of the US Department of Veterans Affairs or the US Armed Forces.

Abbreviations used: AFHS: CDC: NMSC: ORH: PCT: TCDD: VA:

Air Force Health Study Centers for Disease Control and Prevention nonmelanoma skin cancer Operation Ranch Hand porphyria cutanea tarda 2,3,7,8-tetrachlorodibenzo-p-dioxin Department of Veterans Affairs

Orange containing 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD).2 Resultant skin diseases have been

Accepted for publication May 5, 2015. Reprint requests: Benjamin H. Kaffenberger, MD, Ohio State University Dermatology, 915 Olentangy River Road, Suite 4000, Columbus, OH 43212. E-mail: Benjamin.Kaffenberger@ osumc.edu. Published online July 22, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. Published by Elsevier. All rights reserved. http://dx.doi.org/10.1016/j.jaad.2015.05.006

1

J AM ACAD DERMATOL

2 Patterson et al

n 2015

a persistent question with one study reporting up to contamination levels varied between 1 and 50 ppm 85% of exposed veterans describing a persistent in individual barrels with an estimated average skin eruption.3,4 An official review has been mean concentration of 13 ppm.2,7 Although conducted by the Institute of Medicine with specific Vietnam serves as the largest organochlorine emphasis on systemic manifestations including exposure historically, contact risks may still persist cancers, fertility, and cardiovascular, metabolic, in occupational settings including paper mills, neurologic, and immunologic parameters of Agent pesticide manufacturing, incineration/combustion, Orange exposure, but with and metallurgy.7 Another little emphasis on skin disprominent large-scale dioxin CAPSULE SUMMARY ease.5 This article provides a exposure occurred in 1976 in Seveso, Italy, when brief description of organoOrganochlorines are highly toxic a chemical manufacturing chlorine use, disease mechachemicals with long half-lives. plant released several nism, and a summary of Human exposure has occurred through tons of organochlorineevidence for dermatologic industrial accidents and defoliation laced chemicals into the surconditions associated with missions during the Vietnam War. rounding towns. Thousands organochlorine exposure. of residential citizens were This systematic review summarizes the METHODOLOGY exposed to high levels of dermatologic evidence of exposure Journal articles were TCDD and numerous longiassociations and offers clinical guidelines searched and selected on a tudinal studies were confor dermatologists. narrative basis to provide an ducted examining the overview of organochlorine effects of dioxins on human history and pathophysiology. beings.5,7 Another highly publicized case of TCDD Skin disease associations were assessed systematitoxicity involved the 2004 assassination attempt cally by 2 investigators (A. T. P., B. H. K.) using on Ukrainian presidential candidate Viktor search terms ‘‘Agent Orange,’’ ‘‘dioxin,’’ ‘‘2,3,7,8Yushchenko, where high dioxin levels led to tetrachlorodibenzo-p-dioxin,’’ OR ‘‘TCDD’’ AND substantial chloracne development (Fig 2).9-11 This ‘‘skin,’’ ‘‘cutaneous,’’ ‘‘rash,’’ ‘‘skin cancer,’’ ‘‘dermaarticle attempts to examine all organochlorine tol*,’’ ‘‘chloracne,’’ ‘‘acne,’’ OR ‘‘porphyria cutanea human exposures described in the literature for tarda’’ (PCT). Abstracts were reviewed by both any available information on cutaneous toxicity in investigators and selected for studies on 1 or more human beings. human beings. References were cross-checked for additional inclusion (Fig 1). A third investigator (D. M. E.) made final inclusion decisions AGENT ORANGE for disagreements. Throughout the course of ORH, almost 20 million gal of Agent Orangeecontaining an estimated 366 kg of TCDDewas applied to over HISTORICAL EXPOSURE 3.6 million acres across south Vietnam.7 The goal Although numerous phenoxyherbicide formulations were used as defoliants in Vietnam and was to decimate vegetation used for enemy food the Korean demilitarized zone, the most and concealment while clearing land near allied prominent involved a 1:1 mixture of n-butyl esbases for easier defense.6 Despite increased effort ters 2,4-dichlorophenoxyacetic acid and 2,4,5to characterize the degree and distribution of trichlorophenoxyacetic acid. This particular mixture dioxin based on military records, quantifying the became known as Agent Orange, as herbicides were extent of individual exposure to Agent Orange identified by colored stripes on the sides of the 55-gal has proved challenging for researchers.2 The 6,7 transport barrels. Agent Orange is now accepted as expensive serum dioxin test, considered to be the gold standard for organochlorine exposure, reference to all military phenoxyherbicides used has only been used by a few high-level evidence during the era. The synthesis of the 2,4,5studies to date because of its high cost and lack trichlorophenoxyacetic acid component from 2,4,5of resultant impact on clinical management. The trichlorphenol generated the highly toxic byproduct Department of Veterans Affairs (VA) does not TCDD, which remained in the mixture. Dioxins are a perform this test as by law the VA presumes all group of lipophilic, biologically active, chlorinated US service branch members who served in aromatic compounds produced during industrial Vietnam or Korea during certain specified time manufacturing reactions that possess long-lasting periods were exposed to Agent Orange, along environmental pollutant capacity.6,8 TCDD d

d

d

J AM ACAD DERMATOL

VOLUME jj, NUMBER j

Fig 1. Systematic review methodology.

with additional military personnel who meet established time and location service criteria.12 Incidental ground troop exposure to Agent Orange appears to have remained minimal because of the limited bioavailability and rapid photochemical degradation of TCDD, and precise delivery of TCDD by airplane spray devices.13 Several studies have demonstrated nearly identical levels of TCDD in the serum of Vietnam-stationed and control US Army veterans and the general public.13-16 Despite this strong evidence, surveys have shown between 25% to 55% of Vietnam veterans believe they were significantly exposed to herbicides during their service and many present to their physicians with concerns about Agent Orange and its possible contribution to their various health problems.3,8,14 Several groups may be at higher risk including ORH and Army Chemical Corps members both of whom personally handled the liquid herbicides. Compared with other Air Force personnel serving concurrently in Southeast Asia without direct Agent Orange exposure, this high-risk population has demonstrated a statistically significant increase in serum TCDD concentration with persistent elevations even 30 to 40 years postexposure in the Air Force Health Study (AFHS).17-19

MECHANISM FOR HUMAN DISEASE TCDD is classified as a human carcinogen with the potential for rapid bodily absorption via inhalation, ingestion, and direct skin contact. It is extremely lipophilic and becomes distributed to all areas of the body.20 The compound is cleared slowly from human beings with a half-life estimated around 7 years, but is dose dependent.5

Patterson et al 3

Mechanistically, dioxins demonstrate their toxic influence by binding to aryl hydrocarbon receptor, a ligand-activated transcription factor. The receptor-ligand complex then migrates to the nucleus where it binds to designated DNA sequences known as xenobiotic-responsive elements and modulates the transcription of target genes.21,22 The skin is a primary focus of these transcription effects, with rapid development of cutaneous hamartomas and associated sebaceous gland atrophy, suggesting possible interference with cutaneous basal stem cell differentiation (Fig 2).9,10,23 Immunohistochemical staining of epithelial walls of these cystic lesions demonstrates focal induction of CYP1A1, the predominant enzyme involved in dioxin metabolism, and repression of several enzymes that regulate sebaceous lipid synthesis.10,22 TCDD has been shown to be nongenotoxic and nonmutagenic in its interaction with human DNA, but TCDD may act as a tumor promoter for other cancer initiators.5,9 A multitude of studies have examined the possible immunologic impact of Agent Orange exposure to Vietnam veterans in the form of dioxin-induced immune dysfunction. Although isolated reports have detailed statistically significant differences in a single immune measure such as immunoglobulin or interleukin levels, there have been no consistent findings of reduced immunologic status after TCDD exposure.5,24,25

SYSTEMATIC REVIEW OF PUBLISHED SKIN DISEASE ASSOCIATIONS Tables I and II review published studies with 2 or greater patients, many of which show substantial weaknesses, particularly strong deviations in skin disease frequency in self-reported Agent Orange exposure or self-reported skin reactions. Table III summarizes all single case reports. The Centers for Disease Control and Prevention (CDC) Vietnam Experience study logged 4817 skin conditions other than acne possibly associated with Agent Orange exposure. Most were not corroborated when a smaller segment was examined by board-certified dermatologists.3 Chloracne Chloracne typically presents with the development of numerous noninflammatory comedo-like lesions interspersed with straw-colored cysts in a distribution most commonly involving the malar crescent surrounding the eyes and periauricular areas with occasional genital and truncal involvement (Fig 3). Gray dyschromia, hypertrichosis, and folliculitis may

4 Patterson et al

J AM ACAD DERMATOL

n 2015

Fig 2. Chloracne. Photographs of Victor Yushchenko before poisoning (A), and 3 months (B) and 3 to 5 years (C) after poisoning with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Reprinted with permission from Sorg et al.9

accompany the distinctive lesions.26-28 Chloracne distinguishes itself from common acne by location, lack of inflammation, prevalence of closed comedones, and histologic absence of sebaceous glands.29 Although the clinical course is variable, in the majority of cases chloracne will usually develop after a 2- to 4-week latency period after dioxin exposure and regress over 6 months to 3 years.18,27 Although chloracne appears to be the most sensitive marker for dioxin-induced disease in human beingsedeveloping in approximately 85% of patients after known toxic encountersethe absence of chloracne does not exclude the possibility of TCDD exposure and severity has not been proven to be dose dependent.5,7 The AFHS found no cases of chloracne among its veterans on physical examination despite increased self-reported incidence; however, the study was not initiated until more than 10 years after veteran exposure.18,27 The time delay between the realization of the health risk of Agent Orange in the Vietnam War and subsequent health studies limit the use of chloracne to differentiate veteran exposure. Based on the AFHS, a current veteran with chloracne should be evaluated for more recent dioxin exposure outside of Agent Orange. Recent studies reporting examination of veterans with continued chloracne in relation to Agent Orange should be viewed with caution. Porphyria cutanea tarda A less common TCDD-associated disorder with dermatologic ramifications is PCT, an abnormality in heme biosynthesis because of uroporphyrinogen decarboxylase deficiency.5 Examination of the

Seveso population surrounding the TCDD contamination radius revealed increased urinary porphyrin excretion in 13 of 60 subjects, but clinical PCT was seen only in a brother and sister with a pre-existing mutant enzyme that provided enhanced genetic susceptibility when combined with dioxin toxicity.30 Similarly, studies of Vietnam veterans have not found a clear increased risk of PCT years after exposure, although some have noted an increase in urine porphyrins without clinical relevance.3,24,31 Overall, PCT appears to be an exceedingly rare manifestation and veterans presenting with symptoms of PCT should be evaluated for other liver diseases. Despite the evidence, PCT is on the list of conditions for eligible veterans to undergo a disability evaluation through the VA. Melanoma and nonmelanoma skin cancer In the majority of human dioxin exposure studies, an increased incidence of skin cancers has not been found. In the AFHS, basal cell carcinoma incidence was significantly increased in non-black ORH members, but that increase was noted only in the military officer group with the lowest serum dioxin levels, arguing against a dosedependent model for nonmelanoma skin cancer (NMSC).14,18,32 Pavuk et al33 detected an increased melanoma incidence in matched ORH comparison groups of US Air Force veterans with background TCDD serum levels. Another study involving ORH veterans showed an increased incidence of melanoma in white ORH members relative to national incidence rates and comparison veterans who toured in Southeast Asia locations not exposed to herbicides.34 A recent study showed increased

J AM ACAD DERMATOL

VOLUME jj, NUMBER j

rates of NMSC in fair-skinned male veterans when compared with the general population, encompassing men and women of all pigmentation types, but the study suffered from several methodological flaws.35 The difference between these 2 distinct risk populations is incorrectly attributed to Agent Orange, but what is more concerning is the statement that 43% of their veterans had chloracne. This is in direct opposition to the AFHS, which was conducted with dermatology confirmation and showed a 0% prevalence of chloracne among Agent Orangeeexposed veterans and was performed years earlier.18,35 Conversely, the dioxinexposed Seveso population has demonstrated no increased susceptibility for melanoma or NMSCs.36 It is possible that with longer postexposure periods this risk factor may become more conclusive or that other factors involved with military service in Southeast Asia may contribute to the dermatologic cancer risk in this population.12,37 As the Agent Orange linkage is still inconclusive in this area, veterans with the aforementioned skin cancers may elect to be officially registered and evaluated through their local VA. Non-Hodgkin lymphoma Non-Hodgkin lymphoma is associated with Agent Orange exposure.38 Although not specifically addressed, cutaneous T- and B-cell lymphomas might conceivably be increased as a result of skin contact. Researchers investigating patients with mycosis fungoides and a history of Agent Orange contact noted a higher prevalence of the palmaris et plantaris presentation subtype and suggested that the disease concentration on the palms and soles may stem from direct herbicide exposure.39 All patients of the appropriate age range given a diagnosis of cutaneous Tand B-cell lymphomas should be queried for potential military service exposure and referred for VA disability claim evaluation when appropriate. Soft-tissue sarcoma Most evidence involving veterans of the Vietnam era does not show an increased risk of all soft-tissue sarcomas.40-42 However, 1 study cited a trend toward increased soft-tissue sarcoma risk when comparing high and low Agent Orange exposure groups, although the increase was nonsignificant.42 Although not strongly supported by the evidence, age-appropriate patients given a diagnosis of leiomyosarcoma, dermatofibrosarcoma protuberans, and other cutaneous and soft-tissue sarcomas (with

Patterson et al 5

the exception of Kaposi sarcoma), should be screened for Vietnam service and referred for VA disability determination. Other In addition, at least 1 epidemiologic study has reported an increased risk of the following skin conditions in association with Agent Orange or TCDD exposure: eczema, benign fatty tumors, milia, epidermoid cysts, rashes not otherwise specified, dyschromias, and skin sensitivity. A summary of these findings is provided in Tables I and II.

LIMITATIONS TO STUDYING VIETNAM EXPOSURES Vietnam veterans have self-reported a higher frequency of chloracne and other skin ailments and communicate many current concerns about those skin problems, yet dermatologic examination findings over 20 years after possible herbicide exposure often do not support the self-reported symptoms.3,18,32,43 From a psychosocial standpoint, psychiatric symptoms are strongly associated with Vietnam service compared with non-Vietnam veterans.3,24,44 Studies have also shown an increase in ‘‘symptom complex’’ scale scores that quantify selfassessed disease severity among veterans who report persistent health symptoms, with the highest scores occurring in veterans who served in Southeast Asia and handled herbicides directly.45 The increased rates of psychiatric comorbidities in this subset of veterans may suggest a potential psychogenic component to some of the health issues encountered after their Vietnam service, and in the case of perceived Agent Orange exposure, self-reporting and apprehension about the long-term effects may be a vehicle for the expression of psychological distress in some instances.46 When evaluating the CDC Vietnam experience study, veterans selfreported an increased incidence of parasitic infections, benign neoplasms, dyschromia, unspecified skin symptoms, rash not otherwise specified, psoriasis, hypertrichosis, and urticaria. However, the same study found only a statistically significant increased prevalence of tinea versicolor, milia, and epidermoid cysts when the same veterans were examined by board-certified dermatologists.3 Furthermore, potential compensation may influence veterans with Agent Orange exposure. Therefore, the dermatologist must be cognizant of the potential psychological and social factors that may contribute to some of these self-reported sequelae while still advocating for the patient.

J AM ACAD DERMATOL

6 Patterson et al

n 2015

Table I. Vietnam War organochlorine exposure studies Cutaneous manifestations: SR/ICD/ pathology/ general examination/ dermatologic examination

No. of exposures/ patients*

No. of controls*

Vietnam AF Health Study18,26,32-34,47-50

1196

1853

AF Veterans in SE Asia but not Vietnam

Prospective cohort

20

10+, 15+ for dioxin assessment

Serum dioxin

SR/dermatologic examination

Vietnam Army Chemical Corps17,51-53

2872

2737

Army Chemical Corps

Prospective cohort

35

28+ for dioxin assessment

Risk modeling; dioxin serum in #70%

ICD

100

NA

Standard US incidences

Retrospective cohort

NA

38+

SR

General examination

Clemens et al Washington, DC VA study35

Jang et al MF study39

Kim et al AO impact on Korean Veterans of Vietnam24

Design

12

192

MF patients, history of AO exposure

Case control

NA

42+

SR

Dermatologic examination

1224

154

Korean Veterans not stationed in Vietnam

Crosssectional

NA

24+

SR with risk modeling confirmation

General examination

Case Series

NA

24+

SR

General examination

Rash/no rash as surrogate

Retrospective cohort

NA

21+

SR

SR

Monozygotic twin not in Vietnam

Retrospective cohort

NA

26+

Presence in SE Asia

SR

Meyer case series54

7

Tamburro Louisville AO registry liver disease study31

45

34

2260

2260

Eisen et al cotwin study of the Vietnam War43

Control strategy

No. of years followed

Start time after exposure (years), last exposure 1971

AO exposure history: Serum dioxin/ chloracne/ SR/risk modeling/ other?

NA

NA

J AM ACAD DERMATOL

Patterson et al 7

VOLUME jj, NUMBER j

Chloracne/ other acne INC (S) on SR32; however, no cases on examination18

PCT No cases

43% of sample

Melanoma and/ or NMSC

Other cutaneous oncologic manifestations, soft-tissue sarcoma, or cutaneous lymphoma

BCC, NMSC, and sun-related SC: INC (S)18,32; melanoma INC (S) in ranch hand compared to controls and in nonoccupational exposed but still measurable33,34

All cancer INC (S) DR (includes NMSC and other skin);

INC (NS) for skin cancer53

All cancer INC (S) but excludes NMSC17 (may include melanoma or lymphoma)

Rash/other Hyperpigmentation INC (S) with dioxin exposure but no difference between comparison subjects32; no consistent abnormalities of immunologic parameters; INC (S) skin bruises, patches, or sensitivity in comparison to controls18; benign skin neoplasms and neoplasms of uncertain behavior INC (S) sporadically, no DR

INC (S) compared to standard rate of normative US adults

12 of 204 cutaneous lymphoma patients with AO exposure INC (NS); other acne INC (NS)

INC (S) uroporphyrin measured, not clinically relevant

Eczema INC (S); seborrheic dermatitis INC (S); neurodermatitis, INC (S)

7-patient series of cutaneous lymphoma No cases

No cases

‘‘All skin conditions’’ as persistent (now) and any time; current INC (S) for now and at anytime; INC (S) with combat exposure DR

Weakness of study, (not including SR data) statistical, attrition, and additional comments

LOE

Dioxin exposure 15+ years out requiring modeling elimination; not always modified by body fat; not powered for rare disease associations.

III

Mortality data only not powered for rare outcomes; no skin examinations

III

Poor matching with normative data without proper adjustment for known risk factors; questionable if 43% of patients in this study diagnosed with chloracne compared to 0% in AFHS Small study, unclear degree of patient exposure; case series with few valuable analyses

III

Selection bias: low participation of noneVietnam Veterans (eg, 34% participation in exposed vs 5% in nonexposed); NS linear trend in exposure status and correlation with small sample of confirmation TCDD test Case series, no statistical analysis Rash of any sort used as surrogate marker for AO exposure; no chloracne in cohort or PCT Evaluated skin collectively as ‘‘all dermatologic conditions’’

III-IV

III

IV

III

III

(Continued)

J AM ACAD DERMATOL

8 Patterson et al

n 2015

Table I. Cont’d

No. of years followed

Start time after exposure (years), last exposure 1971

AO exposure history: Serum dioxin/ chloracne/ SR/risk modeling/ other?

Cutaneous manifestations: SR/ICD/ pathology/ general examination/ dermatologic examination

No. of exposures/ patients*

No. of controls*

CDC Vietnam Experience Study, telephone vol 23

9324

8989

Non-SE Asia exposure

Retrospective cohort

NA

12+

Presence in SE Asia

SR

CDC Vietnam Experience Study, telephone vol 33

2490

1972

Non-SE Asia exposure

Retrospective cohort

NA

12+

Presence in SE Asia

Dermatologic examination

CDC selected cancer study (NHL)38

1157

1776

Case control

NA

13+

Presence in SE Asia

ICD

CDC selected cancer study (sarcoma)46

342

1776

Age-matched men with NHL regardless of Veteran status Age-matched men with NHL regardless of Veteran status

Case control

NA

13+

Presence in SE Asia

ICD

Kang et al soft tissue sarcoma (1987)42

217

599

Pathology matched, within military

Case control

NA

4+

Risk modeling

Pathology

Kang et al soft tissue sarcoma (1986)41

234

13496

Pathology matched, within military

Case control

NA

0+

Risk modeling

ICD

Control strategy

Design

J AM ACAD DERMATOL

Patterson et al 9

VOLUME jj, NUMBER j

Chloracne/ other acne

PCT

Dec (S)

INC (S); all acne - INC NS after active duty

Rare, INC (NS); other acne, no difference

Melanoma and/ or NMSC

Other cutaneous oncologic manifestations, soft-tissue sarcoma, or cutaneous lymphoma

No cases clinically, 1 patient with urinary porphyrins

Rash/other Only active duty: INC (S) skin infections; after active duty: parasitic infections, benign neoplasms, dyschromia, unspecified skin disorder, or rash NOS INC (S); during active and after: urticaria, psoriasis, and hypertrichosis, INC (S) Tinea versicolor, milia, and epidermoid cysts were the only findings that were INC (S); 68 conditions had basically similar frequency between groups; other conditions INC with OR [ 1.3 but NS include LSC, psoriasis, grade IV acne, candida infections, actinic keratosis, poikiloderma of civatte, and dyshidrosis

No difference

INC (S), in nonHodgkin lymphoma, did not specify cutaneous lymphoma separately No difference in analysis of all sarcomas

INC but NS for STS if stratified by combat exposure in region of Vietnam with high AO use No association of STS and Vietnam Exposure

Weakness of study, (not including SR data) statistical, attrition, and additional comments

LOE

A priori designated chloracne, PCT, hypertrichosis, hyperpigmentation, infectious disease of skin, and skin cancer as areas of interest; a total of 4817 skin conditions other than acne reported by 4105 veterans

III

Sampling bias likely minimal; performed by 6 blinded Board certified dermatologists; stronger than previous CDC telephone survey

III

Outdated diagnostic tools; no specific mention of cutaneous lymphoma

III

Most cases diagnosed as sarcoma NOS; separately analyzed by military status, stationing, and AO risk factors without any associations; included leiomyosarcomas and DFSP in analysis of all sarcoma Inexact method of determining AO exposure; overall, no association of STS and Vietnam exposure Analyzed all STS together; disqualified nearly 40% of ICD diagnoses as unlikely; blinded pathologist to military service

III

III

III

(Continued)

J AM ACAD DERMATOL

10 Patterson et al

n 2015

Table I. Cont’d

Stellman et al legionnaire study45

Levy AO exposure and PTSD44

No. of exposures/ patients*

No. of controls*

2858

3933

1957 screened (6)

25

Control strategy

Design

No. of years followed

Start time after exposure (years), last exposure 1971

AO exposure history: Serum dioxin/ chloracne/ SR/risk modeling/ other?

Cutaneous manifestations: SR/ICD/ pathology/ general examination/ dermatologic examination

Legionnaires not serving in SE Asia

Crosssectional

NA

12+

Risk modeling

SR

Random veteran

Retrospective cohort

NA

17+

Chloracne

SR, general examination confirmation

Weigand case series55

16

NA

Case series

NA

9+

SR

Dermatologic examination

Bogen case series4

78

NA

Case series

10

8+

SR

General examination

AF, Air Force; AO, Agent Orange; CDC, Centers for Disease Control and Prevention; DIF, direct immunofluorescence; ICD, International Classification of Diseases; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; LOE, level of evidence; MF, mycosis fungoides; NHL, non-Hodgkin lymphoma; NMSC, nonmelanoma skin cancer; NS, nonsignificant; OR, odds ratio; PCT, porphyria cutanea tarda; PTSD, posttraumatic stress disorder; S, significant; SE, Southeast; SR, self-reported; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzop-dioxin. *Largest sample allocated in given study.

CONCLUSION Dermatologists encounter many questions as to organochlorine exposure on current health problems. Although the evidence does not support significant TCDD effects in veterans who did not serve in the Army Chemical Corps or ORH, it is not the role of the dermatologist to make this determination. Although evidence has demonstrated a correlation between organochlorine contact and the acute cutaneous development of chloracne, many other skin diseases remain contentious. Age-appropriate patients given a diagnosis of PCT, cutaneous lymphomas, and softtissue sarcomas should be screened for industrial exposure or military service with subsequent VA

referral for Agent Orangeeexposed veterans to undergo disability claim evaluation based on impairment level. Although there is some evidence, it is far from conclusive in skin diseases such as eczema, benign fatty tumors, epidermoid cysts, rash not otherwise specified, dyschromia, skin sensitivity, melanoma, and NMSCs. Even less support exists for psoriasis, seborrheic dermatitis, neurodermatitis, and hypertrichosis. For these and other skin conditions, physicians can assure patients that it is unlikely that their skin disease is associated with Agent Orange while still encouraging the veteran to see their local VA environmental health coordinator for official registration if concerns persist.

J AM ACAD DERMATOL

Patterson et al 11

VOLUME jj, NUMBER j

Chloracne/ other acne Other acne INC (NS)

PCT

Melanoma and/ or NMSC

Other cutaneous oncologic manifestations, soft-tissue sarcoma, or cutaneous lymphoma

‘‘Skin rash with blisters,’’ INC (S)

Rash/other

Burning sensation and transient redness in 2 of 16 patients, no final diagnosis 85% with a resistant skin rash; reported photosensitivity (53%), arthralgias (71%), hypersomnolence (44%), extreme fatigue (80%), paresthesias (60%), and dizziness (69%); intercellular IgG, IgA, and IgM on DIF of 1 patient

7.

8. 9.

10.

11.

LOE III

Venereal disease, photosensitivity, change in skin color INC (S); dose-response seen in benign fatty tumors, skin symptoms scale, rash, and eczema INC (S); DR in handlers of herbicides

6 of 1957 patients diagnosed

REFERENCES 1. Allen AM, Taplin D, Lowy JA, Twigg L. Skin infections in Vietnam. Mil Med. 1972;137(8):295-301. 2. Stellman JM, Stellman SD, Christian R, Weber T, Tomasello C. The extent and patterns of usage of Agent Orange and other herbicides in Vietnam. Nature. 2003;422:681-687. 3. Health status of Vietnam veterans. II. Physical health. Centers for Disease Control Vietnam Experience Study. JAMA. 1988; 259(18):2708-2714. 4. Bogen G. Symptoms in Vietnam veterans exposed to Agent Orange. JAMA. 1979;242(20):2391. 5. Institute of Medicine, Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. Veterans and Agent Orange: update 2012. Washington (DC): National Academy Press; 2012. 6. Schecter A, McGee H, Stanley JS, Boggess K, Brandt-Rauf P. Dioxins and dioxin-like chemicals in blood and semen of

Weakness of study, (not including SR data) statistical, attrition, and additional comments

Simply screened veterans for chloracne for other purposes; not diagnosed by dermatologist

IV

Case series; no statistical analysis, no final diagnosis, just descriptive

IV

Case series; no statistical analysis, no final diagnosis, just descriptive; not performed by dermatologist

IV

American Vietnam veterans from the state of Michigan. Am J Ind Med. 1996;30:647-654. Dunagin WG. Cutaneous signs of systemic toxicity due to dioxins and related chemicals. J Am Acad Dermatol. 1984; 10(4):688-700. Frumkin H. Agent Orange and cancer: an overview for clinicians. CA Cancer J Clin. 2003;53:245-255. Sorg O, Zennegg M, Schmid P, et al. 2,3,7,8Tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites. Lancet. 2009;374:1179-1185. Saurat JH, Kaya G, Saxer-Sekulic N, et al. The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko. Toxicol Sci. 2012;125(1):310-317. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin in US Army Vietnam-era veterans. Centers for Disease Control Veterans Health Studies. JAMA. 1988;260(9):1249-1254.

J AM ACAD DERMATOL

12 Patterson et al

n 2015

Table II. Industrial and broad populatin organochloride exposure studies

Study and location/cohort, where applicable NIOSH studies NIOSH: 12 sites56,57

NIOSH crosssectional study: NJ and MO58,59

Monsanto, Nitro, WV (1948-1969) Nitro crosssectional60,61

No. of exposures No. of or patients* controls* 5172

400

Control strategy

Undefined Age-matched US males

260

Design

Exposure history: Time Chloracne, SR, (years) employment, between location, or exposure No. of medical and years records followed assessment

SR, general examination, ICD, dermatologic examination, health records, laboratory studies

Retrospective cohort

NA

11+

Employment

Health records

Retrospective Age, sex, cohort race, and location matched to SR occupational nonexposure

NA

15+

Employment

SR, general examination

754

NA

NA

Crosssectional

NA

30+

Employment

Incident reports

Nitro crosssectional, Moses62,63

226

NA

NA

Crosssectional

NA

10+

Employment, SR

SR, dermatologic examination

Nitro cohort64

204

Retrospective cohort

NA

10+

Employment, SR

General examination

Dow Chemical, Midland, MI (1964) Dow crosssectional, Cook65

Dow crosssectional, Bond66,67

163

Current or former employees with no TCDD processing association

61

NA

NA

Crosssectional

NA

16

Employment

Dermatologic examination

2072

NA

NA

Crosssectional

NA

20+

Employment

Dermatologic examination, ICD

J AM ACAD DERMATOL

Patterson et al 13

VOLUME jj, NUMBER j

Chloracne

PCT

Lymphoma, NS difference; STS, INC (S) in subcohort [1 year TCDD exposure57

11% of exposed cohort developed chloracne (393/3,538)56

INC (S) in highest stratum of serum TCDD58

121 cases following TCDD exposure of 754 employees60 10+ yr f/u: Residual chloracne in 31% of exposed, with an additional 21% reporting history of chloracne (52% total history)63 At 10+ yr f/u: I NC (S) for chloracne vs nonexposed cohort64

Cutaneous oncology

INC (S) in total exposure cohort; INC (S) in [1 yr exposure subcohort57

NS difference all skin cancer occurrence

Melanoma

Other comments

LOE (IA-IV) III

INC (S) TCDD exposure score among chloracne vs. nonchloracne cases in exposure cohort56

III

None reported; NS difference subclinical PCT or uroporphyrinuria59

STS, no difference; 1 death from malignant fibrous histiocytoma61

III

NS difference for all cancer occurrence rates60

NS difference all skin cancer occurrence64

Histopathologic evidence of chloracne: INC (S) for persistent vs. history and persistent vs. no history groups62

III

INC (S) for actinic elastosis vs. control64

III

III

49/61 exposed to TCDD developed chloracne, NS MT INC at 16 yr f/u65 Exposed cohort of 2,072 workers: definite chloracne in 215 cases (10.4%) and probable chloracne in 110 cases (5.3%)67

All cancer

NMSC (BCC and SCC)

1 STS death

III

(Continued)

J AM ACAD DERMATOL

14 Patterson et al

n 2015

Table II. Cont’d

Study and location/cohort, where applicable Dow cohort

68-70

No. of exposures or No. of patients* controls* Control strategy 2187

Design

No. of years followed

Time (years) between exposure and assessment

Exposure history: Chloracne, SR, employment, location, or medical records

SR, general examination, ICD, dermatologic examination, health records, laboratory studies

Undefined USwhite male population, SMR risk estimates

Retrospective cohort

NA

30+

Employment

SR, health records

Undefined Mortality rates obtained using German national rates

Retrospective cohort

NA

34+

Employment, SR

ICD, general examination

BASF Germany (1953) BASF mortality71,72

169

BASF morbidity73

158

161

Unexposed workers at same factory

Retrospective cohort

NA

35+

Employment, SR

SR, health records

BASF TCDD concentrations74,75

138

102

Hamburg laboratory workers without dioxin exposure

Retrospective cohort

NA

35+

Employment, SR

SR, health records, dermatologic examination

Cross-sectional

30+

NA

Employment

General examination, laboratory samples

NA

12+

SR

SR, general examination, dermatologic examination

NA

14+

Location

SR, general examination

Czech Republic (1965-1968)76-79

55

NA

NA

Times Beach, MO (1971) Times Beach, Pilot80,81

68

36

Times Beach, Anergy82,83

154

155

Low-risk TCDD Retrospective exposure cohort based on survey responses Retrospective Similar mobile cohort home residents nearby without TCDD exposure

J AM ACAD DERMATOL

Patterson et al 15

VOLUME jj, NUMBER j

Chloracne

PCT

Exposed cohort of 2,187 workers: chloracne in 245 cases70

2 STS deaths, INC MT (NS)

Chloracne documented in 114/169 exposure cohorts71; None reported72 History of chloracne in 168 exposed cohort: severe 52 cases, moderate or ‘‘erythema’’ 61 cases, no evidence 45 cases

None

All cancer

NS difference all cancer morbidity

20% (11/55) at 10 years of follow-up79

NMSC (BCC and SCC)

Melanoma I: INC (NS)

NS difference all cancer mortality

NS difference all cancer mortality

No Chloracne (N = 139); Moderate Chloracne (N = 49); Severe Chloracne 56 cases; DR mean TCDD conc and chloracne severity

95% of exposed (52/55) at 10 yr f/u79; 2/13 cases with persistent chloracne at 30 yr f/u and INC (S) serum TCDD conc77,78

Cutaneous oncology

Other comments

LOE (IA-IV) III

In exposed workers with chloracne, mean TCDD serum level was 30.5 ppt vs. 6.0 ppt in nonexposed control69

III

NS difference all skin cancer MT71

INC (S) illness episodes relating to skin diseases in exposed vs. control; DR INC (S) for illness rates with chloracne severity and TCDD conc73 INC (S) correlation between higher mean TCDD concentrations and increased chloracne severity75 Reduced skin microvascular reactivity and increased endothelial dysfunction in 15 TCDDexposed vs 14 controls76

III

III

IV

NS difference in anergy in exposed vs. unexposed

III

INC (S) anergy in exposed vs. unexposed83; repeat testing 1988 NS difference in anergy in exposed vs. unexposed82

III

(Continued)

J AM ACAD DERMATOL

16 Patterson et al

n 2015

Table II. Cont’d

Study and location/cohort, where applicable Austrian factory (1969-1975)84-86

Austrian case series87-90

No. of exposures or No. of patients* controls* Control strategy 159

2

Undefined Control A: nearby nonchemical workers; Control B: local cement workers

NA

NA

Design

No. of years followed

Time (years) between exposure and assessment

Exposure history: Chloracne, SR, employment, location, or medical records

SR, general examination, ICD, dermatologic examination, health records, laboratory studies

Retrospective cohort

NA

21+

SR

SR

Case series

NA

NA

Chloracne

Dermatologic examination

Seveso (Italy) ICMESA (1976)91,92 Zone A Mdn serum TCDD: 447 ppt36,93-101

723

181,574

Local unexposed population

Prospective cohort

20+

\1

Location

General examination, dermatologic examination, laboratory studies

Zone B Mdn serum TCDD: 94 ppt36,93-101

4831

181,574

Local unexposed population

Prospective cohort

20+

\1

Location

General examination, dermatologic examination, laboratory studies

31,643

181,574

Local unexposed population

Prospective cohort

20+

\1

Location

General examination, dermatologic examination, laboratory studies

10

20

Zone A without chloracne (n = 10) and non-ABR (n = 10)

Retrospective cohort

NA

12+

Location

Health records, laboratory studies

Seveso, mortality, adult103,104

30,703

167,391

Location matched

Retrospective cohort

10+

\1

Location

ICD, general examination, health records

Sevesoyouth (1-19 years of age)105,106

19,637

100,000

Age-matched (1-19 years at time of incident) in area

Retrospective cohort

8+

\1

Location

ICD, general examination, health records

Zone R Mdn serum TCDD: 48 ppt36,93-101

Sevesoserum TCDD concentrations102

J AM ACAD DERMATOL

Patterson et al 17

VOLUME jj, NUMBER j

Chloracne 1996 Cohort out of 159 Exposed: SR history in 50 cases, Observed Chloracne in 16 cases85

PCT

Cutaneous oncology

All cancer

NMSC (BCC and SCC)

Melanoma

None reported84

Mdn TCDD level per g blood lipid in 9 chloracne patients of 340 pg vs. 16-18 pg in 21 nonchloracne controls86 7-9% of TCDD elimination from the body occurs via skin with no alteration after petrolatum90

Patient 1 - Severe chloracne had TCDD value 144,000 pg/g; Patient 2 - Mild chloracne had TCDD value 26,000 pg/g

All Zones 193 chloracne cases, 192 had resolved at 9 yr f/u95; Zone A - 61 cases \1 yr post-exposure100 All Zones - 193 chloracne cases, 192 had resolved at 9 yr f/u95; Zone B - 9 cases \1 yr postexposure100 All Zones - 193 chloracne cases, 192 had resolved at 9 yr f/u95; Zone C - 64 cases \1 yr post-exposure100 Non-DR Inc (NS) in chloracne cohort vs. controls; suggested that children more prone to chloracne at lower TCDD levels

No reported STS

I at 20-year follow-up: INC (NS)

No reported STS

I at 20-year follow-up: NS difference

I at 20-year I: 9 STS cases, follow-up: INC (NS) 20-year NS difference follow-up; MT: 4 STS deaths, no difference, 25-year follow-up

I: INC (NS) 20-year follow-up

I: INC (NS) 20-year follow-up; MT:INC (NS) 25-year follow-up

Contact dermatitis in 447 total cases (all zones)93,97

LOE (IA-IV) III

IV

III

I: DEC (NS) I: DEC (NS) 20-year 20-year follow-up; follow-up MT: no difference 25 yr f/u

III

I: DEC (NS) I: DEC (NS) 20-year 20-year follow-up follow-up; MT: DEC (NS) (25-year follow-up)

III

III

MT: STS INC (NS)

186 chloracne cases in cohort105; 0.6-1.2% chloracne findings at 2 yr f/u cross-section 7,382 Seveso children (age 11-14)106

Other comments

NS difference for all cancer mortality NS difference for all cancer mortality105

III

MT: INC (NS)

No difference in acne occurrence rate106

III

(Continued)

J AM ACAD DERMATOL

18 Patterson et al

n 2015

Table II. Cont’d

Study and location/cohort, where applicable

No. of exposures or No. of patients* controls* Control strategy

Seveso Women’s Health Study107,108

981

Sevesochloracne95,109

146

182

Baccarelli et al, Seveso110

101

211

Various authors, Seveso30,111-114

Coalite, Derbyshire, UK (1968)115-118

Various

Undefined

Various

NA

Design

No. of years followed

Time (years) between exposure and assessment

Exposure history: Chloracne, SR, employment, location, or medical records

SR, general examination, ICD, dermatologic examination, health records, laboratory studies

Retrospective cohort

NA

20

Location

General examination, dermatologic examination, laboratory studies

Area agematched (ABR and non-ABR) with no skin lesions

Retrospective cohort

NA

1

Chloracne

General examination, dermatologic examination, laboratory studies

Area agematched without chloracne

Retrospective cohort

NA

17+

Chloracne

SR, dermatologic examination, laboratory studies

Various

Various

Various

Various

Various

\1116-118; 10+115

Medical records

Health records, dermatologic examination

Various

79

NA

NA

Case series

NA

1599

NA

NA

Cross-sectional

NA

22+

Employment

Health records, laboratory samples

9

NA

NA

Case series

NA

\1

Chloracne

Dermatologic examination

Miscellaneous occupational/ accidental Aylward et al, New Zealand119

Passarini et al, case series29

J AM ACAD DERMATOL

Patterson et al 19

VOLUME jj, NUMBER j

Chloracne

PCT

DR INC (S) in chloracne with INC serum TCDD conc108

INC (S) chloracne rate each cohort location (A,B,R) vs. non-ABR control; INC (S) chloracne rate A vs. B and A vs. R INC (S) plasma TCDD conc associated with chloracne; NS association for chloracne and age younger than 8, light hair/eye color 0 Chloracne cases in clean-up workers111; Chloracne in 12/22 patients in Reggiani Cohort114 79 chloracne cases after factory exposure116-118; 50% of chloracne cases had persistent dermatologic evidence at 10 yr f/u115 None

9 cases of chloracne - 8 with shared exposure to vacation resort, 1 shoemaker

2 cases of PCT in genetically predisposed family of 66 after TCDD30,113

Cutaneous oncology

All cancer

NMSC (BCC and SCC)

Melanoma

Other comments

LOE (IA-IV)

Mdn lipidadjusted TCDD level for AB cohort 56 ppt with Zone A mdn (272 ppt) 5 3 higher than Zone B mdn (47 ppt)107 Chloracne cohort noted to have higher rates of gastrointestinal complaints (NS)

III

No difference in urticaria or eczema in chloracne vs. control

III

NS difference in peripheral neuropathy in 152 chloracne cohort vs. control112

III

III

IV

Estimated TCDD serum concentrations \300 ppt over entire exposed cohort

III

IV

(Continued)

J AM ACAD DERMATOL

20 Patterson et al

n 2015

Table II. Cont’d

Study and location/cohort, where applicable

No. of exposures or No. of patients* controls* Control strategy

Pelclova et al, Croatia120

11

NA

Tang et al, Chinese factory121

12

Sterling and Hanke, Ukraine122

3

NA

Ryan and Schecter, Russia123

34

NA

Coenraads et al, China124

16

12

Wolf and Karmaus, daycare, Germany125 Jung et al, Hamburg, Germany126

221

189

170

NA

Jansing and Korff, Germany127

8

RodriguezPichardoet al, Spanish Oil128

9

Exposure history: Chloracne, SR, employment, location, or medical records

SR, general examination, ICD, dermatologic examination, health records, laboratory studies

Case series

NA

40+

Retrospective cohort

NA

6+

NA

Case series

NA

NA

Retrospective cohort without control

NA

Group C, nonexposed factory workers; Group D, healthy controls

Cohort

NA

Unexposed daycare employees

Cross-sectional

NA

NA

Cross-sectional

NA

NA

NA

Case series

NA

15+

Chloracne

Dermatologic examination, laboratory samples

NA

NA

Case series

NA

7+

Chloracne

Dermatologic examination, laboratory samples

12

NA

Design

No. of years followed

Time (years) between exposure and assessment

Age-matched men with no history of exposure or skin disease

Unknown

32+

Not stated

20+

Not stated

Employment

General examination, laboratory samples

Chloracne

Dermatologic examination, genomic studies

Chloracne

Dermatologic examination, laboratory samples

Employment

SR

Employment

Dermatologic examination, laboratory samples

Employment

SR, general examination, laboratory samples SR, general examination, laboratory samples

Employment

J AM ACAD DERMATOL

Patterson et al 21

VOLUME jj, NUMBER j

Chloracne

PCT

All 11 patients had residual chloracne evidence

12 chloracne cases documented in control following pre-2002 occupational exposure to dioxins Severe chloracne development in 2 cases, mild chloracne in 1 case History of chloracne development in 29/34 patients; Reported persistent chloracne in 25/34 patients Of 16 exposed cohorts, 7 developed chloracne

8 cases of chloracne development after occupational TCDD exposure 9 cases of chloracne development after TCDD exposure via contaminated olive oil; all had resolved 7+ yrs f/u

All cancer

NMSC (BCC and SCC)

Melanoma

Other comments

LOE (IA-IV)

Mean TCDD level in 11 patients elevated at 274 pg/g 40+ years after exposure INC (S) in expression of AhR, CYP1A1, GSTA1, c-fos, and TGF-alfa in chloracne cohort vs. control

IV

III

IV

None reported

Of 170 exposed cohorts, 27 reported a history of chloracne development

Cutaneous oncology

None reported

Increased TCDD serum levels did not correlate with chloracne

III

TCDD serum levels decreased (NS) from exposed chloracne to exposed nonchloracne to factory nonexposed to healthy control INC (S) in hypoergy risk among exposed cohort

III

INC coproporphyrinuria in 68/170 exposed cohort; no relationship between adipose TCDD conc and coproporphyrinuria Elevated TCDD level in all 8 patients with chloracne history 15+ years after exposure Hypertrichosis in 1/9 cases; hyperpigmentation in 2/9 cases

III

III

IV

IV

(Continued)

J AM ACAD DERMATOL

22 Patterson et al

n 2015

Table II. Cont’d

Study and location/cohort, where applicable Manzet al, Hamburg, Germany129

No. of exposures or No. of patients* controls* Control strategy 1,583

Fitzgerald et al, Binghamton, NY130

482

Kaposi sarcoma case control131-133

50

Undefined West German registry for MT with augmented 3417 local male gas workers NA NA

50

Matched controls

Design

No. of years followed

Time (years) between exposure and assessment

Exposure history: Chloracne, SR, employment, location, or medical records

SR, general examination, ICD, dermatologic examination, health records, laboratory studies

Retrospective cohort

NA

7+

Employment

General examination, health records

Cross-sectional

NA

3+

Employment

SR, ICD, health records

Case control

NA

Unknown

Medical records SR

158

NA

NA

Cross-sectional

NA

Not stated

Employment

General examination, ICD

Cook135

4

NA

NA

Case series

NA

Variable

Employment

Health records

Oliver laboratory workers136

3

NA

NA

Case series

NA

3+

Employment

Dermatologic examination, health records

73

NA

NA

Cross-sectional

NA

Variable

Employment

SR, general examination, laboratory samples

Bishop and Jones, NHL134

Poland137

BCC, Basal cell carcinoma; ICMESA, Industrie Chimiche Meda Societ
a Azionaria; MO, Missouri; NA, not available; NIOSH, National Institute for Occupational Safety and Health; NJ, New Jersey; NMSC, nonmelanoma skin cancer; PCT, porphyria cutaneatarda; PPT, parts per trillion; SCC, squamous cell carcinoma; SMR, standardized mortality ratio; SR, self-reported; US, United States. *Largest sample allocated in given study.

J AM ACAD DERMATOL

Patterson et al 23

VOLUME jj, NUMBER j

Chloracne

PCT

None reported

Cutaneous oncology 1 NHL case

Chloracne status not assessed

MT: INC (NS) in men vs. controls; No difference in women vs. controls

NS difference in 2 cases cancer incidence NMSC or mortality reported

Chloracne status not assessed

Melanoma

Other comments

LOE (IA-IV) III

1 case reported

INC (S) in skin pigmentation changes; rash/ dermatitis in 20%; acne in 5.8%; 4 dx contact dermatitis/other eczema, 2 dx sebaceous gland disease

III

III

5 possible TCDD exposures (4 hair dye, 1 Vietnam) among 50 Kaposi sarcoma cases 2 cases of NHL of scalp in men with severe chloracne 4 cases STS (2 malignant fibrous histiocytomas, 1 fibrosarcoma, 1 liposarcoma)

Chloracne noted in population but not numerically described Chloracne documented in 2/4 cases, possible in other 2 cases Chloracne documented in 2/3 cases initially but had resolved at 3 yrs f/u Chloracne documented in 13 of 73 exposed workers (18%)

All cancer

NMSC (BCC and SCC)

IV

IV

None reported

2 cases of hirsutism reported

IV

None reported; 1 worker with uroporphyrinuria

Hypertrichosis in 16/73 cases; hyperpigmentation in 30/73 cases; acne in 48/73 cases

III

J AM ACAD DERMATOL

24 Patterson et al

n 2015

Fig 3. Chloracne. Photographs demonstrating noninflammatory comedo-like chloracne lesions distributed on the right melolabial cheek (A) and back of neck (B and C). Images (B) and (C) courtesy of the Department of Defense (public domain).

Table III. Single case reports of organochlorine exposure TCDD/Agent Orange exposure

Author

Sorg et al

9

Ehrlich et al138 McConnell et al139

Years from exposure

Exposure

Disease reported

TCDD assassination

Serum TCDD

0-3

Agent Orange, Vietnam TCDD industrial

Self-report

28

Kinetics and toxicology of acute poisoning/chloracne Chronic acquired dyskeratotic papulosis

Truck driver, possible exposure to TCDDcontaminated dust Self-report

10

Angiosarcoma, PCT, and mild chloracne

14

Chemist synthesizing dioxins

36

Chloracne, blisters, keloids, and abscesses; recurrent foot infections, sympathetic neuropathy and localized anhidrosis Chloracne on exposed areas and back; headaches

Fleck140

Agent Orange, Vietnam

Schecter and Ryan141

TCDD

PCT, Porphyria cutanea tarda; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. 12. US Department of Veterans Affairs. Vietnam veterans and Agent Orange independent study course. Veterans Health Initiative. Updated June 2008. Available at: http:// www.publichealth.va.gov/docs/vhi/VHIagentorange_text508. pdf. Accessed June 14, 2015. 13. Young AL, Giesy JP, Jones PD, Newton M. Environmental fate and bioavailability of Agent Orange and its associated dioxin during the Vietnam War. Environ Sci & Pollut Res. 2004;11(6):359-370. 14. Buffler PA, Ginevan ME, Mandel JS, Watkins DK. The Air Force health study: an epidemiologic retrospective. Ann Epidemiol. 2011;21:673-678.

15. Kahn PC, Gochfeld M, Nygren M, et al. Dioxins and dibenzofurans in blood and adipose tissue of Agent Orange-exposed Vietnam veterans and matched controls. JAMA. 1998;259:1661-1667. 16. Young AL. TCDD biomonitoring and exposure to Agent Orange: still the gold standard. Environ Sci & Pollut Res. 2004; 11(3):143-146. 17. Kang HK, Dalager NA, Needham LL, et al. Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam. Am J Ind Med. 2006;49(11): 875-884.

J AM ACAD DERMATOL

VOLUME jj, NUMBER j

18. Air Force Health Study. 2005b. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides. 2002 Follow-up Examination Results. Brooks AFB (TX): Epidemiologic Research Division, Armstrong Laboratory. Available at: http://www.nap.edu/ openbook.php?record_id=11590&page=88. Accessed June 14, 2015. 19. Pavuk M, Patterson DG Jr, Turner WE. Serum concentrations of TCDD and other dioxin-like compounds in US Air Force veterans of Operation Ranch Hand. Chemosphere. 2014;102:18-23. 20. Hites RA. Dioxins: an overview and history. Environ Sci Technol. 2011;45:16-20. 21. Ikuta T, Namiki T, Fujii-Kuriyama Y, Kawajiri K. AhR protein trafficking and function in the skin. Biochem Pharmacol. 2009; 77:588-596. 22. Sorg O. AhR signaling and dioxin toxicity. Toxicol Lett. 2014; 230:225-233. 23. Panteleyev A, Bickers D. Dioxin-induced chloracneereconstructing the cellular and molecular mechanisms of a classic environmental disease. Exp Dermatol. 2006;15:705-730. 24. Kim JS, Lim HS, Cho SI, Cheong HK, Lim MK. Impact of Agent Orange exposure among Korean Vietnam veterans. Ind Health. 2003;41:149-157. 25. Baccarelli A, Mocarelli P, Patterson DG Jr, et al. Immunologic effects of dioxin: new results from Seveso and comparison with other studies. Environ Health Perspect. 2002;110: 1169-1173. 26. Burton JE, Michalek JE, Rahe AJ. Serum dioxin, chloracne, and acne in veterans of Operation Ranch Hand. Arch Environ Health. 1998;53(3):199-204. 27. Tindall JP. Chloracne and chloracnegens. J Am Acad Dermatol. 1985;13:539-558. 28. Suskind RR. Chloracne, ‘‘the hallmark of dioxin intoxication’’. Scand J Work Environ Health. 1985;11(3):165-171. 29. Passarini B, Infusino SD, Kasapi E. Chloracne: still cause for concern. Dermatology. 2010;221:63-70. 30. Doss M, Sauer H, von Tiepermann R, Colombi AM. Development of chronic hepatic porphyria (porphyria cutanea tarda) with inherited uroporphyrinogen decarboxylase deficiency under exposure to dioxin. Int J Biochem. 1984; 16(4):369-373. 31. Tamburro CH. Chronic liver injury in phenoxy herbicide-exposed Vietnam veterans. Environ Res. 1992;59:175-182. 32. Wolfe WH, Michalek JE, Miner JC, et al. Health status of Air Force veterans occupationally exposed to herbicides in Vietnam. I. Physical health. JAMA. 1990;264(14):1824-1831. 33. Pavuk M, Michalek JE, Schecter A, Ketchum NS, Akhtar FZ, Fox KA. Did TCDD exposure or service in Southeast Asia increase the risk of cancer in Air Force Vietnam veterans who did not spray Agent Orange? J Occup Environ Med. 2005; 47(4):335-342. 34. Akhtar FZ, Garabrant DH, Ketchum NS, Michalek JE. Cancer in US Air Force veterans of the Vietnam War. J Occup Environ Med. 2004;46(2):123-136. 35. Clemens MW, Kochuba AL, Carter ME, Han K, Liu J, Evans K. Association between Agent Orange exposure and nonmelanotic invasive skin cancer: a pilot study. Plast Reconstr Surg. 2014;133(2):432-437. 36. Pesatori AC, Consonni D, Rubagotti M, Grillo P, Bertazzi PA. Cancer incidence in the population exposed to dioxin after the ‘‘Seveso accident’’: twenty years of follow-up. Environ Health. 2009;8(39):1-11. 37. Boffetta P, Mundt KA, Adami HO, Cole P, Mandel JS. TCDD and cancer: a critical review of epidemiologic studies. Crit Rev Toxicol. 2011;41(7):622-636.

Patterson et al 25

38. The Selected Cancers Cooperative Study Group. The association of selected cancers with service in the US military in Vietnam. I. Non-Hodgkin’s lymphoma. Arch Intern Med. 1990; 150(12):2473-2483. 39. Jang MS, Jang JG, Han SH, et al. Clinicopathological features of mycosis fungoides in patients exposed to Agent Orange during the Vietnam War. J Dermatol. 2013;40:606-612. 40. The Selected Cancers Cooperative Study Group. The association of selected cancers with service in the US military in Vietnam. II. Soft-tissue and other sarcomas. Arch Intern Med. 1990;150(12):2485-2492. 41. Kang HK, Weatherbee L, Breslin PP, Lee Y, Shepard BM. Soft tissue sarcomas and military service in Vietnam: a case comparison group analysis of hospital patients. J Occup Med. 1986;28(12):1215-1218. 42. Kang H, Enzinger FM, Breslin P, Feil M, Lee Y, Shepard B. Soft tissue sarcoma and military service in Vietnam: a case-control study. J Natl Cancer Inst. 1987;79(4):693-699. 43. Eisen SA, Goldberg J, True WR, Henderson WG. A co-twin control study of the effects of the Vietnam War on the self-reported physical health of veterans. Am J Epidemiol. 1991;134(1):49-58. 44. Levy CJ. Agent Orange exposure and posttraumatic stress disorder. J Nerv Ment Dis. 1988;176(4):242-245. 45. Stellman SD, Stellman JM, Sommer JF Jr, et al. Health and reproductive outcomes among legionnaires in relation to combat and herbicide use in Vietnam. Environ Res. 1988;47:150-174. 46. Robinowitz R, Roberts WR, Dolan MP, et al. Carcinogenicity and teratogenicity vs. psychogenicity: psychological characteristics associated with self-reported Agent Orange exposure among Vietnam combat veterans who seek treatment for substance abuse. J Clin Psychol. 1989;45(5):718-728. 47. Michalek JE, Pavuk M. Diabetes and cancer in veterans of Operation Ranch Hand after adjustment for calendar period, days of spraying, and time spent in SE Asia. J Occup Environ Med. 2008;50(3):330-340. 48. Ketchum NS, Michalek JE, Burton JE. Serum dioxin and cancer in veterans of Operation Ranch Hand. Am J Epidemiol. 1999; 149:630-639. 49. Michalek JE, Ketchum NS, Check IJ. Serum dioxin and immunologic response in veterans of Operation Ranch Hand. Am J Epidemiol. 1999;149(11):1038-1046. 50. Michalek JE, Wolfe WH, Miner JC, Papa TM, Pirkle JL. Indices of TCDD exposure and TCDD body burden in veterans of Operation Ranch Hand. J Expo Anal Environ Epidemiol. 1995; 5(2):209-223. 51. Cypel Y, Kang H. Mortality patterns of Army chemical corps occupationally exposed to herbicides in Vietnam. Ann Epidemiol. 2010;20:339-346. 52. Kang HK, Dalager NA, Needham LL, et al. US Army chemical corps Vietnam veterans health study: preliminary results. Chemosphere. 2001;43:943-949. 53. Dalager NA, Kang HK. Mortality among Army Chemical Corps veterans. Am J Ind Med. 1997;31:719-726. 54. Meyer KM. Incidence of CTCL in Vietnam veterans. Dermatol Nurs. 2002;14(1), 42, 45, 52. 55. Weigand DA. Agent Orange and skin rashea different experience. JAMA. 1980;243(14):1422-1423. 56. Piacitelli L, Marlow D, Fingerhut M, Steenland K, Sweeney MH. A retrospective job exposure matrix for estimating exposure to 2,3,7, 8-tetrachlorodibenzo-p-dioxin. Am J Ind Med. 2000;38(1):28-39. 57. Fingerhut MA, Halperin WE, Marlow DA, et al. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-pdioxin. N Engl J Med. 1991;324:212-218.

26 Patterson et al

58. Sweeney MH, Calvert GM, Egeland GA, Fingerhut MA, Halperin WE, Piacitelli LA. Review and update of the results of the NIOSH medical study of workers exposed to chemicals contaminated with 2,3,7,8-tetrachlorodibenzodioxin. Teratog Carcinog Mutagen. 1997-1998;17(4-5):241-247. 59. Calvert GM, Sweeney MH, Fingerhut MA, Hornung RW, Halperin WE. Evaluation of porphyria cutanea tarda in U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Am J Ind Med. 1994;25(4):559-571. 60. Collins JJ, Strauss ME, Levinskas GJ, Conner PR. The mortality experience of workers exposed to 2,3,7,8-tetrachlorodibenzo-pdioxin in a trichlorophenol process accident. Epidemiology. 1993; 4(1):7-13. 61. Zack JA, Suskind RR. The mortality experience of workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident. J Occup Med. 1980;22(1):11-14. 62. Moses M, Prioleau PG. Cutaneous histologic findings in chemical workers with and without chloracne with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Am Acad Dermatol. 1985;12(3):497-506. 63. Moses M, Lilis R, Crow KD, et al. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: comparison of findings with and without chloracne. Am J Ind Med. 1984;5(3):161-182. 64. Suskind RR, Hertzberg VS. Human health effects of 2, 4, 5 T and its toxic contaminants. JAMA. 1984;251:2372-2380. 65. Cook RR, Townsend JC, Ott MG, Silverstein LG. Mortality experience of employees exposed to 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD). J Occup Med. 1980;22(8):530-532. 66. Bond GG, McLaren EA, Lipps TE, Cook RR. Update of mortality among chemical workers with potential exposure to the higher chlorinated dioxins. J Occup Med. 1989;31(2): 121-123. 67. Bond GG, McLaren EA, Brenner FE, Cook RR. Incidence of chloracne among chemical workers potentially exposed to chlorinated dioxins. J Occup Med. 1989;31(9):771-774. 68. Burns CJ, Collins JJ, Budinsky RA, et al. Factors related to dioxin and furan body levels among Michigan workers. Environ Res. 2008;106(2):250-256. 69. Collins JJ, Budinsky RA, Burns CJ, et al. Serum dioxin levels in former chlorophenol workers. J Expo Sci Environ Epidemiol. 2006;16(1):76-84. 70. Bodner KM, Collins JJ, Bloemen LJ, Carson ML. Cancer risk for chemical workers exposed to 2,3,7,8-tetrachlorodibenzop-dioxin. Occup Environ Med. 2003;60:672-675. 71. Zober A, Messerer P, Huber P. Thirty-four-year mortality follow-up of BASF employees exposed to 2,3,7,8-TCDD after the 1953 accident. Int Arch Occup Environ Health. 1990;62(2):139-157. 72. Thiess AM, Frentzel-Beyme R, Link R. Mortality study of persons exposed to dioxin in a trichlorophenol-process accident that occurred in the BASF AG on November 17, 1953. Am J Ind Med. 1982;3(2):179-189. 73. Zober A, Ott MG, Messerer P. Morbidity follow up study of BASF employees exposed to 2,3,7, 8-tetrachlorodibenzop-dioxin (TCDD) after a 1953 chemical reactor incident. Occup Environ Med. 1994;51(7):479-486. 74. Ott MG, Zober A, Germann C. Laboratory results for selected target organs in 138 individuals occupationally exposed to TCDD. Chemosphere. 1994;29(9-11):2423-2437. 75. Ott MG, Messerer P, Zober A. Assessment of past occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin using blood lipid analyses. Int Arch Occup Environ Health. 1993; 65(1):1-8.

J AM ACAD DERMATOL

n 2015

76. Pelclova D, Prazny M, Skrha J, et al. 2,3,7,8-TCDD exposure, endothelial dysfunction and impaired microvascular reactivity. Hum Exp Toxicol. 2007;26(9):705-713. 77. Pelclova D, Fenclova Z, Preiss J, et al. Lipid metabolism and neuropsychological follow-up study of workers exposed to 2,3,7,8- tetrachlordibenzo- p-dioxin. Int Arch Occup Environ Health. 2002;75 (Suppl):S60-S66. 78. Pelclova D, Fenclova Z, Dlaskova Z, et al. Biochemical, neuropsychological, and neurological abnormalities following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Arch Environ Health. 2001;56(6):493-500. 79. Pazderova-Vejlupkova J, Lukas E, Nemcova M, Pıckova J, Jirasek L. The development and prognosis of chronic intoxication by tetrachlordibenzo-p-dioxin in men. Arch Environ Health. 1981;36(1):5-11. 80. Webb K, Evans RG, Stehr P, Ayres SM. Pilot study on health effects of environmental 2,3,7,8-TCDD in Missouri. Am J Ind Med. 1987;11(6):685-691. 81. Stehr PA, Stein G, Webb K, et al. A pilot epidemiologic study of possible health effects associated with 2,3,7,8tetrachlorodibenzo-p-dioxin contaminations in Missouri. Arch Environ Health. 1986;41(1):16-22. 82. Evans RG, Webb KB, Knutsen AP, et al. A medical follow-up of the health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzop-dioxin. Arch Environ Health. 1988;43(4):273-278. 83. Hoffman RE, Stehr-Green PA, Webb KB, et al. Health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. JAMA. 1986;255(15):2031-2038. 84. Neuberger M, Rappe C, Bergek S, et al. Persistent health effects of dioxin contamination in herbicide production. Environ Res. 1999;81(3):206-214. 85. Neuberger M, Kundi M, J€ager R. Chloracne and morbidity after dioxin exposure (preliminary results). Toxicol Lett. 1998; 96-97:347-350. 86. Neuberger M, Landvoigt W, Derntl F. Blood levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin in chemical workers after chloracne and in comparison groups. Int Arch Occup Environ Health. 1991;63(5):325-327. 87. Valic E, Jahn O, P€apke O, Winker R, Wolf C, R€ udiger WH. Transient increase in micronucleus frequency and DNA effects in the comet assay in two patients after intoxication with 2,3,7,8-tetrachlorodibenzo- p-dioxin. Int Arch Occup Environ Health. 2004;77(5):301-306. 88. Geusau A, Schmaldienst S, Derfler K, P€apke O, Abraham K. Severe 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) intoxication: kinetics and trials to enhance elimination in two patients. Arch Toxicol. 2002;76(5-6):316-325. 89. Geusau A, Abraham K, Geissler K, Sator MO, Stingl G, Tschachler E. Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and laboratory effects. Environ Health Perspect. 2001;109(8):865-869. 90. Geusau A, Tschachler E, Meixner M, P€apke O, Stingl G, McLachlan M. Cutaneous elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Br J Dermatol. 2001;145(6):938-943. 91. Boyd AS, Neldner KH, Naylor M. 2,3,7,8-Tetrachlorodibenzop-dioxin-induced porphyria cutanea tarda among pediatric patients. J Am Acad Dermatol. 1989;21(6):1320-1321. 92. Del Corno G, Montesarchio E, Fara GM. Problems in the assessment of human exposure to tetrachlorodibenzodioxin (TCDD): the marker chloracne. Eur J Epidemiol. 1985;1(2): 139-144. 93. Signorini S, Gerthoux PM, Dassi C, et al. Environmental exposure to dioxin: the Seveso experience. Andrologia. 2000;32(4-5):263-270.

J AM ACAD DERMATOL

VOLUME jj, NUMBER j

94. Needham LL, Gerthoux PM, Patterson DG Jr, et al. Serum dioxin levels in Seveso Italy population in 1976. Teratog Carcinog Mutagen. 1997;17:225-240. 95. Assennato G, Cervino D, Emmett EA, Longo G, Merlo F. Follow-up of subjects who developed chloracne following TCDD exposure at Seveso. Am J Ind Med. 1989;16(2):119-125. 96. Leads from the MMWR. Preliminary report: 2,3,7,8tetrachlorodibenzo-p-dioxin exposure to humanseSeveso, Italy. JAMA. 1989;261(6):831-832. 97. Caputo R, Monti M, Ermacora E, et al. Cutaneous manifestations of tetrachlorodibenzo-p-dioxin in children and adolescents. Follow-up 10 years after the Seveso, Italy, accident. J Am Acad Dermatol. 1988;19(5 Pt 1):812-819. 98. Centers for Disease Control (CDC). Preliminary report: 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure to humanse Seveso, Italy. MMWR Morb Mortal Wkly Rep. 1988;37(48): 733-736. 99. Seveso after five years. Lancet. 1981;2(8249):731-732. 100. Bisanti L, Bonetti F, Caramaschi F, et al. Experiences from the accident of Seveso. Acta Morphol Acad Sci Hung. 1980;28(1-2): 139-157. 101. Pocchiari F, Silano V, Zampieri A. Human health effects from accidental release of tetrachlorodibenzo-p-dioxin (TCDD) at Seveso, Italy. Ann N Y Acad Sci. 1979;320:311-320. 102. Mocarelli P, Needham LL, Marocchi A, et al. Serum concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin and test results from selected residents of Seveso. Italy. J Toxicol Environ Health. 1991;32(4):357-366. 103. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. Ten-year mortality study of the population involved in the Seveso incident in 1976. Am J Epidemiol. 1989;129(6):1187-1200. 104. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. Mortality in an area contaminated by TCDD following an industrial incident. Med Lav. 1989;80(4):316-329. 105. Bertazzi PA, Zocchetti C, Pesatori AC, et al. Mortality of a young population after accidental exposure to 2,3,7,8tetrachlorodibenzodioxin. Int J Epidemiol. 1992;21(1):118-123. 106. Homberger E, Reggiani G, Sambeth J, Wipf HK. The Seveso accident: its nature, extent and consequences. Ann Occup Hyg. 1979;22(4):327-367. 107. Eskenazi B, Mocarelli P, Warner M, et al. Relationship of serum TCDD concentrations and age of exposure for female residents of Seveso, Italy. Environ Health Perspect. 2004;112:22-27. 108. Eskenazi B, Mocarelli P, Warner M, et al. Seveso Women’s Health Study: does zone of residence predict individual TCDD exposure? Chemosphere. 2001;43(4-7):937-942. 109. Caramaschi F, del Corno G, Favaretti C, Giambelluca SE, Montesarchio E, Fara GM. Chloracne following environmental contamination by TCDD in Seveso, Italy. Int J Epidemiol. 1981; 10(2):135-143. 110. Baccarelli A, Pesatori AC, Consonni D, et al. Health status and plasma dioxin levels in chloracne cases 20 years after the Seveso, Italy accident. Br J Dermatol. 2005;152(3):459-465. 111. Assennato G, Cannatelli P, Emmett E, Ghezzi I, Merlo F. Medical monitoring of dioxin clean-up workers. Am Ind Hyg Assoc J. 1989;50(11):586-592. 112. Barbieri S, Pirovano C, Scarlato G, Tarchini P, Zappa A, Maranzana M. Long-term effects of 2,3,7,8-tetrachlorodibenzop-dioxin on the peripheral nervous system: clinical and neurophysiological controlled study on subjects with chloracne from the Seveso area. Neuroepidemiology. 1988;7(1):29-37. 113. Strik JJ, Janssen MM, Colombi AM. The incidence of chronic hepatic porphyria in an Italian family. Int J Biochem. 1980; 12(5-6):879-881.

Patterson et al 27

114. Reggiani G. Acute human exposure to TCDD in Seveso. Italy. J Toxicol Environ Health. 1980;6(1):27-43. 115. May G. Tetrachlorodibenzodioxin: a survey of subjects ten years after exposure. Br J Ind Med. 1982;39(2):128-135. 116. May G. Chloracne from the accidental production of tetrachlorodibenzodioxin. Br J Ind Med. 1973;30(3):276-283. 117. Jensen NE, Sneddon IB, Walker AE. Tetrachlorobenzodioxin and chloracne. Trans St Johns Hosp Dermatol Soc. 1972;58(2): 172-177. 118. Jensen NE. Chloracne: three cases. Proc R Soc Med. 1972;65: 687-688. 119. Aylward LL, Bodner KM, Collins JJ, et al. TCDD exposure estimation for workers at a New Zealand 2,4,5-T manufacturing facility based on serum sampling data. J Expo Sci Environ Epidemiol. 2010;20:417-426. 120. Pelclova D, Fenclova Z, Urban P, et al. Chronic health impairment due to 2,3,7,8-tetrachloro-dibenzo-p-dioxin exposure. Neuro Endocrinol Lett. 2009;30(1):219-224. 121. Tang NJ, Liu J, Coenraads PJ, et al. Expression of AhR, CYP1A1, GSTA1, c-fos and TGF-alpha in skin lesions from dioxin-exposed humans with chloracne. Toxicol Lett. 2008; 177(3):182-187. 122. Sterling JB, Hanke CW. Dioxin toxicity and chloracne in the Ukraine. J Drugs Dermatol. 2005;4(2):148-150. 123. Ryan JJ, Schecter A. Exposure of Russian phenoxy herbicide producers to dioxins. J Occup Environ Med. 2000;42(9):861-870. 124. Coenraads PJ, Olie K, Tang NJ. Blood lipid concentrations of dioxins and dibenzofurans causing chloracne. Br J Dermatol. 1999;141(4):694-697. 125. Wolf N, Karmaus W. Effects of inhalative exposure to dioxins in wood preservatives on cell-mediated immunity in day-care center teachers. Environ Res. 1995;68(2):96-105. 126. Jung D, Konietzko J, Reill-Konietzko G, et al. Porphyrin studies in TCDD-exposed workers. Arch Toxicol. 1994;68(9):595-598. 127. Jansing PJ, Korff R. Blood levels of 2,3,7,8tetrachlorodibenzo-p-dioxin and gamma-globulins in a follow-up investigation of employees with chloracne. J Dermatol Sci. 1994;8(2):91-95. 128. Rodriguez-Pichardo A, Camacho F, Rappe C, Hansson M, Smith AG, Greig JB. Chloracne caused by ingestion of olive oil contaminated with PCDDs and PCDFs. Hum Exp Toxicol. 1991; 10(5):311-322. 129. Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet. 1991;338(8773):959-964. 130. Fitzgerald EF, Weinstein AL, Youngblood LG, Standfast SJ, Melius JM. Health effects three years after potential exposure to the toxic contaminants of an electrical transformer fire. Arch Environ Health. 1989;44(4):214-221. 131. Vineis P, Zahm SH. Immunosuppressive effects of dioxin in the development of Kaposi’s sarcoma and non-Hodgkin’s lymphoma. Lancet. 1988;1(8575-6):55. 132. Hardell L, Eriksson M. HIV infection and dioxin exposure: risk factors for Kaposi sarcoma and malignant lymphoma? Lancet. 1988;1(8585):591. 133. Hardell L, Moss A, Osmond D, Volberding P. Exposure to hair dyes and polychlorinated dibenzo-p-dioxins in AIDS patients with Kaposi sarcoma: an epidemiological investigation. Cancer Detect Prev Suppl. 1987;1:567-570. 134. Bishop CM, Jones AH. Non-Hodgkin’s lymphoma of the scalp in workers exposed to dioxins. Lancet. 1981;2(8242):369. 135. Cook RR. Dioxin, chloracne, and soft tissue sarcoma. Lancet. 1981;1(8220 Pt 1):618-619. 136. Oliver RM. Toxic effects of 2,3,7,8 tetrachlorodibenzo 1,4 dioxin in laboratory workers. Br J Ind Med. 1975;32(1):49-53.

28 Patterson et al

137. Poland AP, Smith D, Metter G, Possick P. A health survey of workers in a 2,4-D and 2,4,5-T plant with special attention to chloracne, porphyria cutanea tarda and psychologic parameters. Arch Environ Health. 1971;22: 316-327. 138. Ehrlich A, Ma AS, Dixon A, Topalovski M, Belsito DV. Chronic acquired dyskeratotic papulosis of the face. Cutis. 2002;69: 469-471.

J AM ACAD DERMATOL

n 2015

139. McConnell R, Anderson K, Russell W, et al. Angiosarcoma, porphyria cutanea tarda, and probable chloracne in a worker exposed to waste oil contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Br J Ind Med. 1993;50:699-703. 140. Fleck H. An Agent Orange: case history. Mil Med. 1985;150(2):103. 141. Schecter A, Ryan JJ. Persistent brominated and chlorinated dioxin blood levels in a chemist: 35 years after dioxin exposure. J Occup Med. 1992;34(7):702-707.