1.2 Compounds considered
Physicians should maintain a high suspicion for acute coccidioidomycosis, especially among patients with a flu-like illness who live in or have visited areas in which disease is endemic. The 29 compounds listed in Table 1 are covered by the assessment. For many of the nationally notifiable infectious diseases, surveillance data are independently reported to various CDC programs. It is not clear whether the children were more susceptible or whether they had heavier exposure to TCDD. The role of providers and health plans in infectious disease surveillance.
Today's Top News (16 Videos)
By December , all 50 states and the District of Columbia had implemented HIV surveillance systems, including both name-based and nonname-based systems. Since , a total of 33 areas 32 states and the U.
CDC will assess the implementation and effectiveness of prevention activities through multiple monitoring systems, including use of new performance indicators for state and local health departments and community-based organizations 1. In the 33 areas 32 states and the U. Listeriosis is a severe but relatively uncommon infection caused by Listeria monocytogenes ; it was made a nationally notifiable disease in Listeriosis is primarily foodborne and occurs most frequently among persons who are older, pregnant, or immunocompromised.
Incidence was highest 1. Molecular subtyping of L. Recent outbreaks have been linked to ready-to-eat meat 1 and unpasteurized cheese 2. In , incidence of listeriosis as reported to FoodNet active surveillance was 0. Department of Agriculture USDA released a national Listeria Action Plan to help guide control efforts by industry, regulators, and public health officials 4.
The number of Lyme disease cases reported for Pennsylvania in included 4, confirmed cases and 1, suspected cases. In contrast, the number of suspected Lyme disease cases reported annually for Pennsylvania during ranged from two to 11 cases.
The increase in the number of suspected cases is attributable to changes in reporting practices. Nevertheless, new prevention tools and techniques are becoming available.
Recent studies indicate that peridomestic tick exposure can be reduced substantially through simple landscaping changes, and bait boxes that deliver rodent-targeted acaricide are now available through certain pest control operators. Other products under development include devices for reducing ticks on deer and naturally occurring fungi that kill ticks on vegetation.
A total of 56 confirmed measles cases, two of them fatal, were reported during by 15 states. Of the 56 cases, 24 were internationally imported, and 19 resulted from exposure to persons with imported infections.
In two other cases, virologic evidence indicated an imported source. The sources for the remaining 11 cases were classified as unknown because no link to importation was detected. Three outbreaks occurred in size range: The case outbreak was in Hawaii and included persons aged 3 months years; this outbreak began simultaneously with a measles outbreak in the Republic of the Marshall Islands, which resulted in cases and three deaths 3.
During , a total of 11, cases of pertussis were reported incidence: This age group had the highest reported incidence Among the other pertussis cases, occurred among children aged months Pertussis continues to cause morbidity in the United States despite high coverage levels for childhood pertussis vaccine.
The incidence of reported pertussis has increased from 2. How much of this increase is caused by increased recognition and better reporting of cases is unclear 1 ,2. Adolescents and adults can become susceptible to disease when vaccine-induced immunity wanes, approximately years after pertussis vaccination 2.
The actual number of pertussis cases especially among adolescents and adults continues to be substantially underreported because the pertussis cough illness resembles other conditions, infected persons might not seek medical care, and availability of reliable diagnostic tests is limited.
Culture for Bordetella pertussis is highly specific but has low sensitivity. Polymerase chain reaction is not standardized, and its use has led to overdiagnosis of pertussis during certain outbreaks 4. New strategies are needed to reduce the burden of pertussis disease in the United States; pertussis vaccines for adolescents and adults are under review by the Food and Drug Administration.
Salmonella isolates are reported by serotype through the Public Health Laboratory Information System. A substantial proportion of S. During , the proportion of multiple drug-resistant strains of S. On March 12, , the World Health Organization WHO issued a global alert for severe acute respiratory syndrome SARS , a potentially fatal new infectious disease that can spread rapidly from person to person and via international air travel.
WHO and its partners, including CDC, initiated a rapid, intensive, and coordinated investigative and control effort that led within 2 weeks to the identification of the etiologic agent, SARS-associated coronavirus SARS-CoV , and to a series of effective containment efforts. Of the total cases reported from the United States, were classified as suspected; 19 were classified as probable; and eight were laboratory confirmed 2. Prolonged, multistate outbreaks of S. A new serotype of Shigella boydii has been reported in the United States and Canada 4.
CDC estimates that approximately 11, cases of invasive GAS disease and 1, deaths occurred nationally during The incidence of invasive GAS infections in the United States has been relatively stable during the past 5 years range: For the third straight year, the proportion of pneumococcal isolates that were drug resistant declined. Of the 3, S. Approximately one in eight In February , the Food and Drug Administration licensed a pneumococcal conjugate vaccine for use in infants and young children.
Vaccine use has reduced rates of invasive pneumococcal disease markedly among children, the vaccine's target age group, and among unvaccinated older persons and has also reduced racial disparities in disease risk 4. During , a total of cases of congenital syphilis were reported As with primary and secondary syphilis, the rate of congenital syphilis has declined sharply in recent years, from a peak of The continuing decrease in the rate of congenital syphilis likely reflects the substantial reduction in the rate of primary and secondary syphilis among women.
Congenital syphilis persists in the United States because a substantial number of women do not receive syphilis serologic testing until late in their pregnancies or not at all. This lack of screening is often related to absent or late prenatal care 2. During , a total of 7, primary and secondary syphilis cases were reported, compared with 6, cases in The rate was the lowest since reporting began in The rate 2.
This disparity between men and women, observed across all racial and ethnic populations, along with reported outbreaks of syphilis in large urban areas among men who have sex with men MSM , indicates that increases in syphilis are continuing to occur among MSM. Rates remain disproportionately high in the South and among non-Hispanic blacks, but these rates are continuing to decline 1, 2.
In , a total of 20 cases of tetanus were reported from 13 states and the District of Columbia. During , a total of 14, tuberculosis TB cases rate: This decline is the smallest since , when TB incidence peaked after a 7-year resurgence 1.
In addition, the rate remains higher than the national interim objective of 3. In descending order, the highest rates per , population were reported among Asians The TB rate among foreign-born persons has declined since from In , the case rate was 8. CDC is collaborating with public health partners to implement TB control initiatives for recent international arrivals and residents along the border between the United States and Mexico and to strengthen TB programs in countries with a high incidence of TB disease 2.
CDC has recently updated its comprehensive national action plan to reflect the realignment of its priorities with the Institute of Medicine report 3 and to ensure that priority prevention activities are undertaken with optimal collaboration and coordination among national and international public health partners 4.
A total of cases of tularemia were reported in , compared with an annual average of cases for the preceding 3 years. Noteworthy were cases involving a child who apparently acquired tularemia from exposure to pet hamsters, an outbreak among commercially distributed prairie dogs, an unusual case of intra-abdominal tularemia in a patient with stomach cancer 1 , and a cluster of pneumonic tularemia cases among lawn-care workers who mowed over a dead rabbit.
In , a total of cases of typhoid fever were reported in the United States. Persons visiting friends and relatives in south Asia appear to be at particular risk, even during short visits 1.
Salmonella Typhi strains with decreased susceptibility to ciprofloxacin are increasingly common in that region and should be treated with alternative antimicrobial agents 2. Typhi outbreaks in the United States are generally limited in size but can cause substantial morbidity; they are most often foodborne and warrant thorough investigation 3.
A sexually transmitted outbreak of typhoid fever has been recognized and reported 4. Compared with , cases declined The Council of State and Territorial Epidemiologists CSTE recommends that all states establish statewide individual varicella case reporting by 1.
The objectives of varicella surveillance at state and national levels are to 1 monitor the epidemiology of varicella by age and place and over time, 2 monitor the impact of widespread and increasing immunization on the epidemiology of varicella, and 3 allow prompt implementation of disease control measures.
In , CSTE recommended that states report varicella deaths to CDC to monitor the impact of routine varicella vaccination on varicella-related mortality 2. In , two states Arkansas and Maryland each reported one varicella death; ages of persons at time of death were 12 and 18 years. Reporting of varicella deaths is incomplete, which limits the usefulness of mortality data in assessing the impact of the varicella vaccination program. CDC encourages states to report varicella deaths, so the risk factors for varicella-related mortality can be identified, and the percentage of deaths that would have been directly preventable by following current recommendations for vaccination can be determined.
During , for the fifth consecutive year, epidemic and epizootic West Nile virus WNV activity occurred in the United States, including a substantial epidemic of neuroinvasive WNV disease in the Great Plains states, widespread perennial reemergence in areas of previous activity, and continued geographic expansion into western states.
The WNV epidemic in the United States was comparable in size to, but focused further west than, the epidemic, which was centered in states along the Mississippi River Valley 1.
Illness onset dates were April December 5; the epidemic peak occurred during the week ending August In , a total of presumptively WNV-viremic blood donors were identified through nationwide blood screening, and investigations were initiated to track birth outcomes among approximately 70 women with WNV illness acquired during pregnancy 2 , 3.
Increased surveillance for human WNV illness cases might have resulted in improved surveillance for other domestic arboviruses of public health importance.
In , WNV activity was reported from 2, counties in 46 states and D. In addition, 12, WNV-infected dead birds were reported from 43 states and D. In , a total of 14 cases of neuroinvasive illness caused by eastern equine encephalitis virus were reported from eight states Alabama, Florida, Georgia, Louisiana, New Jersey, North Carolina, South Carolina, and Virginia , equaling the maximum number reported to CDC in any year during In addition, a large eastern equine encephalitis epizootic among equines cases and including dogs two cases and other veterinary species 18 cases was reported in 19 states.
During , a median of four mean: Case definitions for infectious conditions under public health surveillance. Additional information available at http: Demographic differences in notifiable infectious disease morbidityUnited States, Framework for evaluating public health surveillance systems for early detection of outbreaks; recommendations from the CDC working group.
Framework for program evaluation in public health. Manual of procedures for the reporting of nationally notifiable diseases to CDC. Manual for the surveillance of vaccine-preventable diseases. Journal of Public Health Management and Practice ;7: Reporting race and ethnicity dataNational Electronic Telecommunications System for Surveillance, Sexually transmitted disease surveillance Ten leading nationally notifiable infectious diseasesUnited States, Updated guidelines for evaluating public health surveillance systems: Use of race and ethnicity in public health surveillance: Endemic, notifiable bioterrorism-related diseases, United States, Emerg Infect Dis ;9: Control of communicable diseases manual.
American Public Health Association; Completeness of notifiable infectious disease reporting in the United States: Am J Epidemiol ; Statewide system of electronic notifiable disease reporting from clinical laboratories: Communicating the threat of emerging infections to the public.
Emerg Infect Dis ;6: Evaluation of reporting timeliness of public health surveillance systems for infectious diseases. BMC Public Health ;4: Koo D, Caldwell B. The role of providers and health plans in infectious disease surveillance. Eff Clin Pract ;2: Koo D, Wetterhall S. Journal of Public Health Management and Practice ;2: Use of race and ethnicity in epidemiologic research: Data management issues for emerging diseases and new tools for managing surveillance and laboratory data. Emerg Infect Dis ;1: Niskar AS, Koo D.
Differences in notifiable infectious disease morbidity among adult womenUnited States, J Womens Health ;7: Automatic electronic laboratory-based reporting of notifiable infectious diseases at a large health system.
Emerg Infect Dis ;8: Surveillance of infectious diseases. Electronic laboratory-based reporting for public health. Military Medicine ; suppl 2: Mandatory reporting of diseases and conditions by health care professionals and laboratories.
Principles and practice of public health surveillance. Oxford University Press; Guidelines for national human immunodeficiency virus case surveillance, including monitoring for human immunodeficiency virus infection and acquired immunodeficiency syndrome.
J Acquir Immune Defic Syndr ; Foodborne botulism in the United States, Emerg Infect Dis ; Botulism in the United States, Botulism in the United States: Ann Intern Med ; Brucella melitensis, abortus, suis , and canis. Human exposure to Brucella abortus strain RBKansas, Brucella abortus strain RB Prevention of laboratory-acquired brucellosis.
Clin Infect Dis ; Changing trends in the epidemiology of human brucellosis in California from to J Infect Dis ; Chancroid epidemiology in New Orleans men. An investigation of genital ulcers in Jackson, Mississippi, with use of a multiplex polymerase chain reaction assay: Etiology of genital ulcers and prevalence of human immunodeficiency virus coinfection in 10 US cities.
Sexually transmitted disease surveillance supplement: Chlamydia Prevalence Monitoring Project, annual report Chlamydia trachomatis infections in female military recruits. N Engl J Med ; A pilot study of chlamydial infection in a national household survey.
Sex Transm Dis ; Prevalance of chlamydial and gonococcal infections among young adults in the United States. Cholera in the United States, Trends at the end of the millennium. J Infect Dis ;, The global resurgence of cholera.
Communicable disease epidemiology and control. Reported cholera in the United Sates, Risk factors for sporadic cryptosporidiosis among immunocompetent persons in the United States from to J Clin Microbiol ; Diagnostic procedures for stool specimens: Surveillance for waterborne-disease outbreaks associated with recreational waterUnited States, Surveillance Summaries, October 22, Risk and control of waterborne cryptosporidiosis. Epidemiology of Cyclospora cayetanensis and other intestinal parasites in a community in Haiti.
Outbreak of cyclosporiasis associated with imported raspberries, Philadelphia, Pennsylvania, The emergence of another tickborne infection in the town area around Lyme, Connecticut: The human ehrlichioses in the United States [Review].
Emerg Infect Dis ;5: Outcome of diagnostic tests using samples from patients with culture-proven human monocytic ehrlichiosis: Risk factors for sporadic giardiasis: Surveillance for waterborne-disease outbreaks associated with drinking waterUnited States, Giardiasis surveillanceUnited States, Increases in fluoroquinolone-resistant Neisseria gonorrhoeae among men who have sex with menUnited States, , and revised recommendations for gonorrhea treatment, Sexually transmitted diseases treatment guidelines, Sexually transmitted diseases surveillance supplement: Gonorrhea in the HIV era: Am J Public Health ; Identification of Haemophilus influenzae serotypes by standard slide agglutination serotyping and PCR-based capsule typing.
J Clin Micro ; Progress toward elimination of Haemophilus influenzae type b disease among infants and childrenUnited States, Haemophilus influenzae type b Hib disease among Amish children in Pennsylvania: Recommendations for use of Haemophilus b conjugate vaccines and a combined diphtheria, tetanus, pertussis, and Haemophilus b vaccine: Hepatitis A virus infections in the United States: Prevention of hepatitis A through active or passive immunization: The diverse patterns of hepatitis A epidemiology in the United Statesimplications for vaccination strategies.
The value of immunization against hepatitis A. Infect Agents Dis ;3: Epidemiology of hepatitis A: Vaccine ;10 suppl 1: Incidence of hepatitis B virus infection in the United States, Incidence and risk factors for acute hepatitis B in the United States, Prevalence of hepatitis B virus infection in the United States: Semin Liver Dis ; The prevalence of hepatitis C virus infection in the United States, through The past incidence of hepatitis C virus infection: Connecticut Agricultural Experiment Station; Bunikis J, Barbour AG.
Laboratory testing for suspected Lyme disease. Med Clin North Am ; Predicting risk of Lyme disease: Malaria surveillanceUnited States, Surveillance Summaries, April 30, Probable transfusion-transmitted malariaHouston, Texas, Progress toward measles eliminationabsence of measles as an endemic disease in the United States.
J Infect Dis ; Suppl 1: National, state, and urban area vaccination levels among children aged monthsUnited States, Molecular epidemiology of measles viruses in the United States, Epidemiology of transmissible diseases after elimination.
Modeling relationships between climate and the frequency of human plague cases in the southwestern United States, Am J Trop Med Hyg ; Plague as a biological weapon: Working Group on Civilian Biodefense [Review].
World Health Organization; Control and prevention of rubella: Identifying risk factors for rubella susceptibility in a population at risk in the United States. The changing epidemiology of rubella in the s: Preparing for congenital rubella syndrome elimination: Q fever in humans and animals in the United States [Review]. Vector Borne and Zoonotic Dis ; Clinical and epidemiologic features of 1, infections [Review].
Q fever control measures: Compendium of animal rabies prevention and control, Human rabies preventionUnited States, Rabies surveillance in the United States during Am Vet Med Assoc Epidemiology of human rabies in the United States, to [Review].
Cases of Rocky Mountain spotted fever in family clustersthree states, Rocky Mountain spotted fever in the United States, Rocky Mountain spotted fever [Review]. National surveillance for Rocky Mountain spotted fever, Laboratory-confirmed shigellosis in the United States, Epidemiological features of a newly described serotype of Shigella boydii.
Arch Pediatrics and Adolescent Medicine ; Concurrent outbreaks of Shigella sonnei and enterotoxigenic Escherichia coli infections associated with parsley: Journal of Food Protection ; Prevention of invasive group A streptococcal disease among household contacts of case patients and among postpartum and postsurgical patients: Active Bacterial Core Surveillance report. Emerging Infections Program Network. Group A streptococcus, preliminary. Epidemiology of invasive group A streptococcus disease in the United States, Invasive group A streptococcal disease: Preventing pneumococcal disease among infants and young children: Impact of childhood vaccination on racial disparities in invasive Streptococcus pneumonias infections in the United States, Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States.
Decline in invasive pneumococcal disease following the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med ; The national plan to eliminate syphilis from the United States. Primary and secondary syphilisUnited States, Sexually transmitted disease surveillance supplement Tetanus surveillanceUnited States, However, because these compounds are extremely persistent, past releases remain in the environment as contaminated soils and sediments and will take decades to decline.
Furthermore, the relative importance of sources varies from one country to another. Today, the main quantified releases are from combustion processes. UNEP has started to collect data from national and regional inventories of dioxin. It became evident that there were no harmonized methods for establishing inventories.
Most inventories cover emissions to the air only; less information is available on releases of residues and products to land and water. Most of the information comes from the Northern Hemisphere, and the sources in developing countries have not been quantified.
Changes in techniques for waste incineration have reduced exposure in industrialized countries, but the role of reservoirs remains to be evaluated.
Iron and steel manufacture is an important contributor in many countries, but not all industrialized countries include this important sector in their inventories. Feed, food-producing animals and food products may become contaminated in various ways, including deposition of emissions from various sources on farmland, burning of contaminated raw material for direct drying, blending of feedstuffs with contaminated products, application of contaminated pesticides, detergents, or disinfectants, contact with wooden materials treated with wood preservatives, application of sewage sludge to fields, flooding of pastures, contamination of water with wastewater and effluents, food processing, or migration from chlorine-bleached packaging material.
As the half-lives of some of these compounds in the environment are decades or longer, the environmental contamination is likely to persist for some time. Food may become contamined via many pathways, including direct deposition from the air onto leafy plants used in feed and ingestion of contaminated soil by herbivores e. Potatoes and carrots can take up these compounds from contaminated soil into their outer layers.
The only plants for which a mechanism for uptake and distribution has been demonstrated are courgette and pumpkin. Feed may also be contaminated European Union, c. Owing to the ubiquity of contamination with PCDDs, PCDFs and coplanar PCBs and the low limits of detection required to identify biologically relevant concentrations, there is substantial uncertainty about the predominant pathways by which these compounds enter the food supply.
During the past few decades, heavy exposure to dioxins and furans has occurred in isolated incidents of contamination or release. Well-studied examples of environmental releases include the exposure of the local population at Seveso, Italy Pocchiari et al.
Heavy exposure, with toxic effects, has also been caused by contaminated foods. Known examples are the contamination of edible oils, such as in the Yusho Japan and Yu-cheng Taiwan food poisoning episodes Rogan et al.
Incidents of lighter contamination, with no known toxic effects, have been reported, which include ingestion of a naturally contaminated feed additive a form of clay which led to elevated concentrations of dioxin in catfish and poultry Rappe et al.
These cases show that food can become contaminated in a variety of ways. After the successful reduction of emissions of PCDDs, PCDFs and coplanar PCBs into the environment in the s, s and s, attention must now be focused on animal feed and the pathways to feed in order to reduce the amounts of these compounds entering the food supply.
As fat is efficiently absorbed from the gastrointestinal tract, dioxin-like compounds administered in a fatty matrix can be expected to pass easily into the blood.
Similarly, mean absorption fractions of 0. Little may be absorbed from more complex matrices such as the diet. After absorption from the gastrointestinal tract, TCDD enters the lymph in the form of chylomicrons Lakshmanan et al. Once in the blood, TCDD-containing chylomicrons are quickly within 1 h cleared from the blood. After clearance of chylomicrons, dioxin-like compounds remain mainly in serum lipoproteins very low-, low- and high-density lipoproteins and bound to serum proteins.
In serum, the distribution of TCDD between lipoproteins and serum proteins is determined by their lipid content. However, higher-substituted dioxins and furans do not partition only in accordance with the lipid content of serum components: For OCDD, almost the opposite situation was observed, i. Furthermore, substantial partitioning of 1,2,3,6,7,8-HeCDD and 1,2,3,4,6,7,8-HpCDD between the serum and erythrocytes has been found, again indicating substantial binding of higher-chlorinated congeners to blood proteins.
As in blood, the distribution of dioxins and furans between serum and organs is determined by lipid partitioning and protein binding. The concentrations of dioxins and furans in blood and adipose tissue correlate well Päpke et al. In the liver, protein binding plays an important role in the uptake of dioxin-like compounds from the blood, even for lower-chlorinated congeners. When rodents are exposed to increasing doses of TCDD, preferential accumulation occurs in the microsomal fraction of the liver, such that the concentration exceeds that in adipose tissue by many fold Allen et al.
The biochemical mechanism behind this phenomenon is as follows. In the case of PCBs, hepatic sequestration depends on substitution at the ortho position, greater substitution resulting in decreasing sequestration. The hepatic sequestration of dioxins, furans and PCBs markedly affects the relative amounts of these compounds in the body body burden. Binary mixtures of dioxins, furans and PCBs show clear interactions with respect to hepatic sequestration. Preferential sequestration of dioxins and furans in liver rather than adipose tissue has also been observed in persons exposed to background concentrations of these compounds Figure 1.
The observed hepatic sequestration is probably due to binding to constitutive rather than induced CYP 1A2 proteins, as, in humans, CYP 1A2 is primarily expressed constitutively and induced in the liver Diliberto et al. A physiologically based pharmacokinetics model showed that induction of Ah receptor-dependent CYP proteins is unlikely to occur in the liver of persons who have been exposed for long periods to background concentrations of TCDD Zeilmaker et al.
Concentrations from Leung et al. T4cdd, sum of tetracholodibenzodioxins; P5cdd, sum of pentachlorodibenzodioxins; H6cdd, sum of hexachlorodibenzodioxins; H7cdd, sum of heptachlorodibenzodioxins; Ocdd, octachlorodibenzodioxin; T4cdf, sum of tetrachlorodibenzofurans; P5cdf, sum of pentachlorodibenzofurans; H6cdf, sum of hexachlorodibenzofurans; H7cdf, sum of heptachlorodibenzofurans; Ocdf, octachlorodibenzofuran Figure 1.
Ration of concentrations of dioxins and furans in human liver and adipose tissue. Rodents excrete dioxins and furans almost exclusively via the bile, the urine being only a minor route of elimination Gasiewicsz et al. The metabolism includes dechlorination, hydroxylation and conjugation Koshakji et al. Humans eliminate dioxins and furans much more slowly than rodents. In one volunteer, the half-life of TCDD ranged from 5. A half-life of 8. Longitudinal, relatively extensive data showed a mean half-life for TCDD of 8.
In these analyses, first-order kinetics was used to estimate the half-lives from the time-dependent decrease in its concentration in blood. This approach is based on the assumptions that the body composition of individuals is constant during the observation period, that elimination is independent of body composition, and that individuals have a constant background rate of intake.
Both groups of authors found that these assumptions were false. In order to correct for them, van der Molen and van der Molen et al. This analysis resulted in in a half-life of 5 years in young adults, 11 years in elderly men and 8 years in year-old men from the data of Michalek et al.
Thus, Michalek et al. The mean half-life of TCDD in middle-aged men is thus 7. Elimination half-lives for polychlorinated dioxins, furans, and coplanar polyclorinated biphenyls.
Coplanar PCBs may induce their own metabolism. Similarly, clear biphasic elimination of 2,3,4,7,8-PeCDF and 1,2,3,4,7,8-HxCDF was observed in Yu-cheng and Yusho patients, indicating that they had been exposed to concentrations well above background for induction of metabolism Ryan et al.
On day 16, these doses resulted in concentrations of 6. On day 21 of gestation, the concentration of TCDD were 4. On day 16 of gestation, there was a good correlation between the fetal and maternal body burden and the fetal body burden and maternal blood concentration, suggesting that, at a critical time, maternal blood concentrations provide an estimate of the concentrations of dioxin in the developing fetus.
On day 16 of gestation, the concentration of TCDD in single fetuses was 1. These concomitant processes can be quantified by physiologically based pharmacokinetics modelling, in which the toxicokinetics of chemicals is described mathematically within a physiological context, i. Arrows indicate the direction of blood flow, into arterial blood and from venous blood the organs Figure 2.
Physiologically based pharmacokinetics model for dioxins and furans. The first physiologically based pharmacokinetics models of dioxin-like compounds 2,3,7,8-TCDF, King et al. However, these models could not describe the hepatic sequestration of dioxin-like compounds, in particular the binding of TCDD to induced hepatic CYP 1A2.
Physiologically based pharmacokinetics modelling has also been used to describe the kinetics of dioxin-like compounds in humans. Assuming that the body burden of dioxin-like compounds is composed mainly of the amounts in the liver and adipose tissue, Carrier et al. In both cases, the exposure was found to have only a limited effect on the long-term body burden.
Zeilmaker and van Eijkeren ; and Zeilmaker et al. Figures 3, 4 and 5 show typical simulations made with this model of the accumulation of TCDD in the human body as expected after a variety of exposure scenarios. TCDD concentration in blood lipid.
Physiologically based pharmacokinetics model of accumulation of TCDD. Effect of transplacental exposure on the body burden after life-long exposure to TCDD see first two panels, Figure 3.
Extra bolus oral dose administered at age of 30 years. Body burden of TCDD expressed in pg. As in second panel, effect of both doses on ratio of area under the curve AUC of concentration-time Fourth panel: Effect of lactation on body burden of mother.
Lactation started at age 25 years and lasted 6 months. The lower line shows the body burden when the partition coefficients of adipose tissue and of milk fat are the same, i. Combined effects of transplacental exposure and lactation on body burden of infant. Lactation as in fourth panel.
Dose-response relationship of the daily dose of TCDD up to age 30 years and the resulting blood lipid concentration. Accompanying metabolic induction factor with respect to basal metabolism. Note the absence of induction of metabolism at background exposure. Cells exposed to chemicals may respond by increasing the activity of metabolizing enzymes, in particular phase I and phase II enzymes enzyme induction.
Although this mechanism can lead to the removal of chemicals with deletorious effects, enzyme induction also has clear disadvantages. As the induced enzymes often have broad substrate specificity, increased activity may increase the metabolism of chemicals other than the inducing compound. After TCDD has diffused into the cell, it binds to the intracellular Ah receptor protein, which is maintained in its ligand inactivated state by complexation with heat shock protein hsp This complex than translocates to the nucleus, where it combines with the Ah receptor nuclear translocator Arnt to a transcription factor, which may bind to a specific DNA enhancer site, the so-called xenobiotic responsive element.
Concurrently, transcription factors bind to gene-specific promotor sites, thereby increasing gene transcription. In concordance with this result, single doses of 0. As shown in Figure 6, whereas the hepatic TCDD concentration increased linearly as a function of the administered dose, the induced protein concentrations increased non-linearly as a function of the hepatic concentration of TCDD, until a maximum was reached.
Data from Tritscher et al. The dose—response characteristics of EROD induction were similar in the two organs. The lowest dose also significantly increased the phosphorylation of Cdc2 cyclin-dependent kinase, a protein associated with the G 2 to M phase transition of cells, in the liver but not in skin DeVito et al.
Whereas induction of acetanilide 4-hydroxylase is limited to the liver DeVito et al. Similar observations were made in rats, in which dose-dependent induction of EROD activity and the amount of CYP 1A1 was observed in the liver, lungs and kidneys of rats given a single dose of 0. As in mice, the induced EROD activity in the lungs and kidneys represented only a small fraction of the corresponding hepatic activity lungs, 0.
Similar observations were made for hepatic methoxyresorufin O -demethylase activity, with a dose-dependent increase in activity in the liver, which correlated well with induced CYP 1A2 protein levels. Although the absolute activity of EROD in the liver was fold higher than that in the lungs, similar dose—response relationships were found in these organs. Epidermal growth factor EGF is a plasma membrane receptor which, after binding a specific ligand, functions as a signal tranducer regulating cellular proliferation.
This effect is mediated by internalization of the ligand—receptor complex and then phosphorylation of intracellular targets by tyrosine kinase.
TCDD is a known inducer of liver tumours in female, but not male, rats Kociba et al. It also induces proliferation of hepatocytes and preneoplastic foci in intact, but not ovariectomized, female rats Lucier et al. This expression may be enhanced by the estrogen receptor—estrogen complex. As a consequence, more TGF- alpha is secreted into the interstitial space in the liver, where it may combine with EGF on the liver cell membrane.
Finally, estrogen metabolism estradiolhydroxylase activity is catalysed by CYP 1A2. From Kohn et al. The stimulation of thyroid metabolism may be compensated by increased amounts of thyroid-stimulating hormone TSH in the blood. When sustained, such compensation may result in chronic stimulation of the thyroid and, ultimatally, thyroid cancer Kohn et al.
At least two forms of glucuronosyltransferase contribute to the activity of T4 UGT: Decreased plasma T4 levels were found after exposure of rats to phenobarbital, 3-methylchlolanthrene or the PCB mixture Aroclor No effect was found on total triiodothyronine T3 van Birgelen et al. This suggests involvement of the Ah receptor in inducing hepatic T4 glucuroni-dation and, consequently, in modulating thyroid hormone metabolism van Birgelen et al.
The concentration of plasma retinol was increased concomitantly. The mechanism behind this effect consists of induction of CYP enzymes, which oxidize retinol and reduce the activity of acyl coenzyme A: Both enzymes participate in the esterification of retinol.
Disturbed biosynthesis of haem may lead to porphyria, a condition in which precursors of haem accumulate in blood and are hence excreted in the urine.
Furthermore, induced acetanilide 4-hydroxylase activity correlated well with induction of accumulation of porphyrins in the liver. Short-term intake of TCDD 0. Again, hepatic CYP 1A2 enzyme activity and total hepatic porphyrin accumulation correlated well. Exposure to PCDDs, PCDFs and coplanar PCBs actually consists of exposure to a mixture of congeners with toxic effects dermal toxicity, immunotoxicity, carcinogenicity, reproductive and developmental toxicity, disruption of endocrine functions similar to those of TCDD, the most toxic congener of this class of compounds.
This finding led to the development of the concept of toxic equivalency factors TEFs. In this concept, the toxic potency of a congener, i. Application of the TEF concept rests on the following assumptions van den Berg et al, , noting that the TEF concept does not apply to toxicity that is not mediated by the Ah receptor and does not take into account modulation of Ah receptor-dependent responses by non-Ah-receptor ligands:.
Derivation of congener-specific TEFs is based on evaluation and interpretation of the results of all available studies of toxicity on the basis of expert judgement. The TEF concept was re-evaluated in van den Berg et al.
Studies of toxicity were placed in the following order of priority: Similarly, Ah receptor-dependent toxic end-points were given priority over biochemical end-points such as enzyme induction.
TEFs for mammals were considered to apply to humans too. When combined with data on residues in matrices such as tissue, soil and water, TEFs allow determination of the toxic equivalents concentration of the residue. In using the TEF concept, it should be kept in mind that non-Ah receptor-mediated toxicity decreased dopamine concentration, effects on retinoid and thyroid hormone concentrations and estrogen receptor binding , shown by some PCBs, is not covered.
Similarly, the TEF concept does not apply to halogenated compounds other than PCDDs, PCDFs and PCBs which show Ah receptor-dependent toxicity brominated and chloro or bromo analogues of PCDDs, PCDFs, naphthalenes, diphenyl ethers, diphenyl toluenes, phenoxyanisoles, biphenyl anisoles, xanthenes, xanthones, anthracenes, fluorenes, dihydroanthracenes, biphenyl methanes, phenylxylyl-ethanes, dibenzothiophenes, quaterphenyls, quaterphenyl ethers and biphenylenes.
For example, antagonistic effects of non-coplanar PCBs have been described on Ah receptor-dependent effects like induction of EROD and fetal cleft palate in mice.
Whereas the currently agreed TEFs are based on toxicological evaluations of dose—response relationships between external exposure, i. The acute toxicity of TCDD and related dioxins and furans substituted in at least the 2, 3, 7 and 8 positions can vary widely between and among species Table 3.
For example, in guinea-pigs, an LD 50 of 0. Explanations for this variation include differences in the Ah receptor, such as size, transformation and binding to the dioxin response element, pharmacokinetics metabolic capacity, tissue distribution and body fat content Geyer et al.
In Ah-responsive rodent species, it is thought that lethality correlates to Ah receptor binding affinity. Although some differences exist between species, other toxic responses observed after single doses of dioxins include haemorrhage in a number of organs, thymic atrophy, reduced bone-marrow cellularity and loss of body fat and lean muscle mass.
The consistent pathological findings included gradual loss of adipose and muscle tissue wasting syndrome , thymic atrophy and gastrointestinal lesions.
All mice were observed for 35 days before necropsy. Decreased body-weight gain, increased liver weight and thymic and splenic atrophy were observed in both strains of mice Birnbaum et al. None of the animals at the lowest dose died, while 8. The toxicity of TCDD and related coplanar chemicals in short-term studies is characterized, depending on the route and species, by similar biological and toxicological effects. In studies of the porphyrinogenic potential of various chlorinated dioxins, furans and coplanar PCBs, groups of five female B6C3F 1 mice were treated on 5 days per week for 13 weeks by gavage with concentrations related by TEFs to doses of TCDD of 0, 0.
Analysis of hepatic tissue for highly carboxylated porphyrins and CYP 1A1 and 1A2 induction indicated that the binding affinity of the congeners to the Ah receptor in vivo was related to CYP 1A2 induction, which was in turn correlated to hepatic porphyrin accumulation. The LOELs associated with significant increases in total hepatic porphyrin content were: Induction of hepatic porphyrins by the mono- ortho -substituted PCBs was greater than that estimated from the TEFs assigned to them, which was considered to be related in part to non-Ah receptor-dependent induction of CYP 2B1 and delta -aminolaevulinic acid synthetase van Birgelen et al.
The deaths occurred only at the highest dose, four females dying during the 13 weeks of treatment and two males and two females dying between 14 and 49 days during the week post-dosing observation period.
The NOEL was thus 0. Groups of six male and six female rats of the same strain were fed diets containing a variety of penta- and hexachlorinated dioxins and dibenzofurans, separately and in a mixture, for 13 weeks: Male and female Fischer rats were given oral doses of TCDD designed to generate a liver concentration of 0. After an initial loading dose of 0. Induction of this gene has not been associated with various treatments designed to induce hepatocellular proliferation Fox et al.
Hepatic EROD activity was significantly increased in all treated groups when compared with controls, with similar induction at the low, intermediate and high doses. When the tumour promoting ability of the three treatments was assessed relative focal volume of ATPase-deficient preneoplastic liver tissue , similar results were obtained after modelling the toxic equivalents for liver with TCDD and the dioxin mixture; however, the response to the latter was about twofold lower at the highest dose.
The authors concluded that TEFs based on enzyme induction in vitro provide only an approximation of the tumour promoting ability of dioxin congeners and gave an overestimate of the response to the HpCDD Schrenk et al. On the basis of the measured end-points deaths, hepatic EROD induction, decreased plasma T4 concentration, haematological indices , the TEF for this congener was estimated to be 0.
In an experiment of a similar design, groups of 20 rats of the same strain were given total toxic equivalents of 0, 0. Whereas there was a significant, dose-dependent increase in hepatic EROD activity even at the lowest toxic equivalents 0.
Overall, the effects seen with the toxic equivalent mixture, TCDD or 1,2,3,6,7,8-HxCDD alone were comparable mortality rate, growth reduction, hepatic enzyme induction, haematological effects , providing support for the TEF and additivity concept for chlorinated dioxins Viluksela et al.
The most sensitive effects, seen at the lowest dose, included hepatic CYP 1A1 and 1A2 induction and significant decreases in thymus weights and hepatic retinol concentration.
At the higher doses, differences in liver, kidney and spleen weights and decreases in plasma T3 and free T4 concentrations were seen. Thyroid hormone status was assessed in rats in a short-term assay for tumour promotion. While there was no effect on T3 concentration, that of serum TSH was increased by about 2. Histological changes in the thyroid included diffuse follicular hyperplasia; in rats at 3. The effects induced were similar to those in rats, including deaths at the highest dose.
The NOEL for changes in organ and body weights and clinical effects was 0. Most of the long-term experiments designed to determine the toxicity of dioxin and coplanar chemicals were conducted with various rodent species or non-human primates. The carcinogenic effects assessed in long-term studies are summarized in Table 4. Dose-dependent increases in the incidence of both ulcerative skin lesions and amyloidosis were observed at the two lower doses and a decreased lifespan in mice at the highest dose.
An increased incidence of liver tumours hepatomas and hepatocellular carcinomas was observed at the intermediate dose, but a similar increase at the highest dose was not significant Tóth et al. Among those reported were ear-duct carcinoma, renal adenocarcinoma, skin angiosarcoma, Leydig-cell adenoma, fibrosarcoma, squamous-cell carcinoma of the skin and lung, glioblastoma, astrocytoma, cholangiocarcinoma and lymphocytic leukaemia. No tumours were found at the lowest dose Van Miller et al.
The Committee noted that the small number of animals used and the high mortality rates limit interpretation of this study. Groups of 50 Sprague-Dawley rats of each sex 86 rats of each sex as vehicle controls were fed diets formulated with TCDD to provide a dose of 0, 0.
Body weight and food consumption were measured throughout the study; haematological examinations and urinary analyses were performed on eight rats of each sex per group after 3, 12 and 23 months.
Serum samples were collected twice during the study. The biochemical and histopathological examinations were extensive. Increased incidences of hepatocellular carcinoma, squamous-cell carcinomas of the lung, hard palate and tongue were observed at the highest dose.
TCDD not only affected the incidence rates of cancer but had additional toxicological effects, particularly at the highest dose, which included increased mortality females only , decreased body-weight gain, splenic and thymic atrophy, hepatic degeneration and necrosis.
On the basis of increased urinary excretion of porphyrins and delta -aminolaevulinic acid and hyperplastic nodules in the liver in females at 0.
Animals at the higher dose showed marginal signs of toxicity Bowman et al. Several short—term assays for genotoxicity with TCDD covering various end-points gave primarily negative results. Thioguanine selection resulted in a weakly positive response Rogers et al. Sister chromatid exchange and micronuclei were found in human lymphocytes treated with TCDD, in the absence or presence of alpha -naphthoflavone Nagayama et al.
TCDD also transformed AdSVimmortalized cells but not primary human epidermal keratinocytes, as revealed by growth in soft agar, and increased foci formation, cell density and the carcinogenic response in nude mice. OCDD did not induce mutations in S. When administered concomitantly with O -tetradecanoylphorbol acetate, TCDD increased the cell transforming capacity of peritoneal macrophages in mice in a dose-dependent manner Massa et al.
TCDD enhanced alpha -naphthoflavone-induced sister chromatid exchange frequency in cultured rat lymphocytes Lundgren et al. It did not induce sister chromatid exchange, micronuclei or chromosomal aberrations in mouse bone marrow Meyne et al.
TCDD increased the mutagenic and recombinogenic activity of N- ethyl- N -nitrosourea in the mouse spot test by twofold Fahrig, In lacI transgenic rats, TCDD increased neither the mutation frequency nor the mutation spectrum in the liver Thornton et al. Similarly, TCDD did change the spontaneous spectrum of H- ras codon 61 point mutations in mouse liver, nor did it affect the mutation spectrum of H- ras mutations in hepatocellular adenomas and carcinomas after treatment of mice with vinyl carbamate Watson et al.
In a three-generation study of reproductive toxicity, male and female Sprague-Dawley rats 16 males and 32 females in the control and high-dose groups; 10 males and 20 females at the low and intermediate doses were maintained on diets containing TCDD designed to deliver a dose of 0, 0. The F 1b and F 2 litters were mated when the animals were about days of age to produce the F 2 and F 3 generations, respectively. Fertility, litter sizes and neonatal survival were severely decreased for animals at the highest dose at the F 0 matings and in ensuing generations at the intermediate dose.
Although slight effects were seen on pup survival and renal morphology at the low dose, they did not occur consistently across all generations. The NOEL was 0. The steady-state body burdens of TCDD of the rats at the two lower doses were estimated to have been 0. After a second breeding, in which 14 treated males and seven treated females at 1. Groups of 10—12 female B6C3F 1 mice were treated by gavage with various dioxin, furan and PCB congeners once every 3 weeks for five dosing periods to assess the survival of autotransplanted endometrial lesions.
Endometrial tissue was transplanted during the second dosing period. Whereas the weights of the lesions appeared to decrease with increasing dose of TCDD, the weights were still higher than those of controls. No significant effects were seen on ovarian or uterine horn weights, but the thymus weights were decreased and the liver weights increased at the two higher doses of PCDF.
The size of the maintenance doses was based on a reported elimination half-life of 3 weeks for adult rats. The dams were killed after weaning, and 20 male pups per group were either assessed at 70 or days of age for sexual development sex organ weights, sperm analysis or bred to untreated females on postnatal day No effects were seen on reproductive performance mating, pregnancy, fertility. At the highest dose, the serum testosterone concentration was decreased at adulthood, and permanent changes in the testicular tubuli were found, including pyknotic nuclei and the occurrence of cell debris in the lumen.
Mounting and intromission latencies were significantly increased at the lowest and highest doses. The rats were killed 24, 48, 56 and 72 h later study termination , and body weight, ovarian weights, ovulation status and serum prolactin, luteinizing hormone and follicle-stimulating hormone were measured.
After 7 months of treatment, the monkeys were bred to untreated males, produced the F 1 generation and were bred again after 27 months on diet. The total amount of TCDD ingested by the mothers was estimated to have been ng after While there was no indication of maternal toxicity at the time, analysis of the monkeys 10 years after termination of the study revealed a dose-dependent increase in the frequency and severity of endometriosis, and three monkeys at the higher dose died due to severe peritoneal endometriosis.
As there was a high concentration of coplanar PCBs in the blood of monkeys in which endometriosis was originally diagnosed, there may have been an unknown source of exposure to PCBs that caused the reported lesions Rier et al.
The average dietary concentration of PCBs was reported to be 7. The average doses of TCDD delivered were 0, 0. Laparoscopic examinations were conducted on all monkeys at 1, 3, 6 and 12 months study termination.
The surviving endometrial strips in animals at the lowest dose actually regressed in size. The serum concentrations of interleukin IL -6 were significantly decreased, while those of IL-6 soluble receptor were increased in monkeys at the highest dose at termination, with a 2. Dioxins, and specifically TCDD, induce a distinct series of developmental effects, including fetal mortality, structural malformations and postnatal functional alterations, in a variety of species at doses below those associated with maternal toxicity.
These effects are thought to be due in part to interactions with the Ah receptor and its related transcriptional factor, ARNT, the expression of which appears to be involved in aspects of normal embryonic development Kozak et al. In most species tested to date, TCDD can induce significant embryolethality early or late resorptions, abortions, stillbirths , which is usually associated with indications of maternal toxicity. The timing of dosing and the age of the embryo or fetus have been shown to be major determinants of TCDD-induced prenatal mortality.
Characteristic, sensitive indications of the teratogenicity of TCDD in responsive strains of mice include induction of cleft palate and hydronephrosis at doses not associated with maternal toxicity.
While cleft palate in the absence of fetal or maternal toxicity usually occurs only in mice, common effects in rats and hamsters include renal malformations, oedema and gastrointestinal haemorrhage. The ability of most coplanar chemicals to induce frank developmental effects is related to their binding affinity to the Ah receptor.
Decreased maternal body-weight gain was seen only in mice treated with TCDD on day 10 of gestation, whereas the relative liver weight was increased at all doses of TCDD. There was a trend towards a decrease in maternal body-weight gain in mice treated with retinoic acid on day 10 and increased relative liver weight after treatment on both days 10 and The increase in relative liver weight seen in mice treated with both chemicals was similar to that seen with TCDD alone.
All treated groups had 6—20 litters. Hydronephrosis was seen in all groups treated with TCDD, with a dose-dependent increase in severity. The median effective dose ED 50 for this lesion was estimated to be 3. Combined treatment with the two chemicals had no effect on either TCDD-induced hydronephrosis or retinoic acid-induced skeletal anomalies, but they had an interactive effect on cleft palate induction. Significant increases in relative liver weights were seen in maternal animals at all doses, but there were no effects on litter size, litter weight or fetal mortality.
Various structural end-points associated with the developing urogenital system of rodents have been shown to be extremely sensitive to perturbation by TCDD and coplanar chemicals. Additional maternal rats were treated with a single oral dose of 0, 0. After this time and until sexual maturity postnatal day , no significant differences were seen for either parameter. Although there was a trend towards decreased plasma testosterone and dihydrotestosterone concentrations in male offspring from postnatal day 32—, none of the changes was significant.
Male offspring from litters in the above study, standardized on postnatal day 1 to five pups of each sex per litter from dams treated with graded doses of TCDD on day 15 of gestation, were also assessed for sexual behaviour on postnatal days 56—63, 70—77 and — While the number of intromissions required before ejaculation was not significantly affected, the number of mounts required before ejaculation was slightly increased in all groups during testing on postnatal days — Hepatic EROD activity, when determined on postnatal day , was not significantly increased at any dose Mably et al.
Male pups isolated after lactation were assessed for various aspects of the development of the reproductive system on postnatal day 32, 39, 63 and juvenile, pubertal, postpubertal and sexually mature, respectively.
Although slight decreases in paired testis weights were observed at all doses except 0. The weight of the right epididymis was decreased in a dose-dependent manner at a maternal dose as low as 0. The weights of the cauda epididymis were lower than those of controls at all doses after puberty postnatal days 63 and No significant effects were seen on cauda epididymal sperm motility or morphology.
The plasma concentration of follicle-stimulating hormone was slightly reduced only on postnatal day 32 at all maternal doses except 0.
When the male offspring were mated with control females on postnatal day 70, no effects were observed on fertility, gestation index, litter size or pup survival Mably et al. Some male pups were retained for assessment of reproductive organ weights and sperm counts at 15 months of age.
On postnatal days 49 and 63, most of the developmental affects in male offspring occurred at the highest dose and included decreased numbers of epididymal sperm postnatal day 49 and 63 and decreased weights of the cauda epididyma postnatal day 63 , ventral prostate and seminal vesicle postnatal day The onset of puberty was delayed by about 2 and 4 days at the two higher doses, respectively.
However, when the results were combined with those of a previous study Gray et al. These effects of low doses of dioxin and coplanar chemicals on the developing male reproductive system are usually not paralleled by decreased reproductive capacity or androgen status.
Also, in general, the effects of TCDD and related coplanar chemicals on the urogenital tract during fetal and neonatal development of rodents, although dependent on the timing and age of the fetus, can be achieved by low doses in utero alone.
Not only male reproductive tract development but also various aspects of male sexual behaviour can be affected by perinatal exposure to low doses of TCDD and coplanar PCBs.
In the experiments by Mably et al. Similarly, in Long Evans rats Gray et al. While demasculinization of sexual behaviour was reproducible in three strains of rat, it was not seen in hamster offspring. Feminization of male sexual behaviour, as assessed by increased intensity and duration of lordosis, was also observed in male Holtzman rats at maternal doses of TCDD as low as 0.
Alteration of defeminization of sexual behaviour by TCDD has been shown to require exposure during lactation or after parturition.
In rats and hamsters, single maternal doses as low as 0. Female offspring from the study of Gray et al. Additional females were mated to control males on postnatal day for assessment of fertility. On postnatal day 70, the age of onset of vaginal opening was delayed in pups of dams at 0. After mating on postnatal day , no significant differences were seen in treated animals with respect to fertility, but the time to pregnancy of offspring of dams at the highest dose was increased by three estrous cycles when compared with controls 4.
Significantly increased numbers of female offspring at 0. Cleft phallus and changes in the urethral opening position have also been observed in rats given other estrogen-like chemicals diethylstilbestrol, RU , estradiol Gray et al.
After parturition, the litters were standardized to four pups of each sex, and the female offspring were monitored for sexual development, estrous cycle and fertility. This effect was thought to be related to the decreased fertility rate of female progeny treated on day 8 when they were entered into a continuous breeding phase five successive litters. Whereas the fertility rates of females treated on day 15 were similar to those of controls up to the fourth litter but significantly reduced by the fifth litter , the fertility rate of females treated on day 8 was reduced by the second litter and throughout the duration of the breeding phase.
Although overall fertility and fecundity in the first litter produced by females treated on day 15 were not affected, the high prevalence of vaginal threads caused greater difficulty in mating with control males, as illustrated by the increased number of mounts without intromission and increased ejaculation latency.
After parturition and lactation, the female offspring were monitored for various developmental landmarks until maturity postnatal day — After mating of the female offspring on postnatal day —, a variety of parameters, including fertility, weaning index, number of implants, litter size and pup survival, were significantly reduced in the treated animals. TCDD treatment also increased the frequency of F 1 female offspring with mild hypospadias or cleft phallus 0.
The litters were standardized on postnatal day 1 to four of each sex, and development was assessed after interim sacrifices on postnatal days 23 males only , 44, 65, —, males only and females only. Duration of gestation, prenatal mortality, litter size and dam weight were not affected by TCDD, and no effect was seen on postnatal pup mortality or pup weight gain throughout the experiment.
TCDD also accelerated the average time to eye opening by about 1 day and decreased thymus weights not dose-dependent on postnatal day 44 in male but not female offspring. No urogenital tract malformations were seen in female offspring, and the time to vaginal opening was not affected. For comparison, the single dose of 0. In a study designed to determine the most sensitive effect of TCDD on the rodent male reproductive system, groups of six pregnant Holtzman rats were given a single oral dose of TCDD at 0, TCDD had no effect on the body-weight gain of dams during gestation or on the weight of male pups during the assessment period.
Maternal treatment with TCDD also had no effect on the relative testis or epididymal weights, daily sperm production, cauda epididymal sperm reserve or serum luteinizing hormone, follicle-stimulating hormone or testosterone concentrations of male offspring.
Semi-quantitative reverse transcription polymerase chain analysis indicated that the levels of androgen receptor mRNA in this organ were significantly reduced in all treated groups on postnatal day 49 but not on postnatal day Administration of TCDD at any dose resulted in a dose-dependent increase in 5 alpha -reductase type 2 mRNA and a decrease in androgen receptor mRNA in the ventral prostate of rats killed on day 49 but not in those killed on day , with no adverse sequelae at the lowest dose of Although the authors postulated that the decreased size of the ventral prostate was due to the decrease in androgen receptor mRNA, previous results Gray et al.
There is currently limited experimental evidence for an Ah receptor-based mechanism of action for dioxin-induced neurotoxicity. Central nervous system functioning and neurobehaviour have been assessed in some animal models. Pregnant Wistar rats were treated by subcutaneous injection with a loading and maintenance dosing regime designed to approximate human perinatal exposure. After an initial dose of TCDD at 0, 1 or 0.
After a slight initial decrease in body weight on postnatal day 7, the body weights of pups of dams on the low-dose regimen were comparable to those of controls. Greater percentages of the TCDD-treated offspring than controls acquired a righting reflex on postnatal day 5 or 6, but they showed a delayed ability to remain on a rotating rod.
The activity of 3-month-old female offspring was significantly reduced after treatment with TCDD in comparison with controls after an amphetamine challenge. Monkeys treated with TCDD showed an increased overall level of behavioural arousal, including increased self-directed behaviour, when compared with controls. No significant relationship was observed between any of the behavioural parameters and the concentration of TCDD in the body fat of the infants. Similar effects were not seen when a second cohort of offspring obtained after the maternal animals had been on control diet for 16 months were tested.
A further group of infant rhesus monkeys one female, four males was obtained after the maternal animals had been on the TCDD-containing diet for Cognitive testing of the monkeys in both groups was conducted when they were about 14 months of age. Monkeys exposed perinatally to TCDD took a significantly longer time to learn the first reversal of a shape discrimination—reversal problem than controls 47 versus 27 trials. No significant effect of TCDD was seen for subsequent reversals up to eight.
In addition, no significant effect was seen on learning of spatial or colour reversal problems or in the ability to respond to a delayed spatial alternation test. The performance of offspring on a shape discrimination—reversal problem was not correlated to the concentration of TCDD in their adipose tissue.
TCDD-induced thymic atrophy has been observed after perinatal exposure in all species examined Holladay et al. TCDD-induced thymic atrophy is probably of less clinical significance in adult animals, as no correlation has been established between effects on the thymus and functional immune suppression.
The reported acute ED 50 values for thymic atrophy in adult animals vary considerably among species: Several hypotheses have been proposed to explain the mechanism by which TCDD induces thymic atrophy. TCDD administered orally at 0. Similar results were obtained when T-cell responsiveness was tested with an antigenic challenge with conalbumin, suggesting that TCDD acts at a time when T cells are in the process of differentiating in response to antigenic challenge, as TCDD had no effect on naïve or resting T cells that had not been challenged with an antigenic stimulus.
On the basis of these results, the authors suggested that the observed immunotoxic effects of TCDD may be mediated partly through the presence of the Fas molecule in activated T cells and that MHC phenotype may also play an important role Rhile et al.
TCDD affects both cellular and humoral immunity. Its effects on T-cell function are characterized by changes in several end-points, including delayed-type hypersensitivity DTH responses, rejection of skin allografts, generation of cytotoxic T lymphocytes and lymphoproliferative responses of lymphocytes to mitogens and specific antigens in vitro.
The effects on T-cell function occur at concentrations three orders of magnitude lower than those that affect thymus cellularity. Species differ in their sensitivity to TCDD, guinea-pigs being more sensitive than rodents. Differences in DTH response have also been observed in the same species challenged with different antigens.
TCDD-induced effects on the cytotoxic T lymphocyte response of spleen cells have been found less consistently. Generation was inhibited at all doses. On the basis of mechanistic studies in vitro, the authors concluded that the cellular basis for suppression of the cytotoxic T lymphocyte response was induction of T-suppressor cells in the thymus which act selectively against the cytotoxic T lymphocyte response Clark et al.
The mechanism by which TCDD affects the cytotoxic T lymphocyte response therefore remains to be elucidated. Specifically, TCDD at a dose as low as 1. Differences among species in the primary response to antigens have also been observed.
The plaque-forming cell response in mice was significantly suppressed, with an ED 50 value of 0. The mechanism responsible for the observed differences between the two species in their response to T cell-dependent and T cell-independent antigens remains to be elucidated Smialowicz et al.
Differences in the response to various antigens after exposure to TCDD have also been observed within the same species. The effects of TCDD on host resistance to various infectious agents, including bacteria, viruses and parasites, has been well documented. Increased mortality in response to S. None of the doses compromised the ability of mice to combat infection by H.
Increased parasitic infestation has been reported after administration of TCDD. The ability of hosts to combat viral infection was compromised at doses of TCDD lower than those that affected resistance to bacteria and parasites.
Mice given an intraperitoneal injection of TCDD at 0. An even lower LOEL of 0. The mortality rates of mice given TCDD was statistically significantly higher than that of controls, but the rate at doses of 0. TCDD did not alter the replication or clearance of the virus in these mice Burleson et al. Young animals are reported to be highly sensitive to prenatal or neonatal exposure to TCDD. The LOEL for increased mortality of offspring due to endotoxin was the lowest dose, that for decreased thymus weight was 2.
A single dose of TCDD at 0. Exposure during both gestation and lactation was required for suppression of the DTH response Gehrs et al. Further experiments with TCDD at 0, 0. Thus, doses of TCDD as low as 0. All rats were killed 3 days after the last feeding. Stimulation of IL-2 production by spleen cells was also reduced, but only in the group treated for days. Both groups showed decreased conconavalin A-induced expression of IL-2 receptors by splenic T-cells in vitro Badesha et al.
In summary, immunotoxic effects of TCDD have been observed in several species at multiple targets in the immune system. The severity of TCDD-induced immunotoxic effects varies among species and depends largely on the end-point investigated. The effects on the thyroid observed in experimental animals after exposure to dioxins or coplanar chemicals usually involve decreases in free and total T4 in serum, with no compensatory effects on TSH or T3 Brucker-Davis, Dose-dependent decreases in plasma T4 concentration were observed in groups of eight female Sprague-Dawley rats given diets supplemented with TCDD at a concentration of 0, 0.
The LOEL was 0. Thyroid hormone status was assessed in rats from a short-term assay for tumour promotion. After initiation with N -nitrosodiethylamine at 70 days of age, female Sprague-Dawley rats were treated by gavage every 2 weeks for 30 weeks with TCDD at doses designed to deliver 0, 0. While there was no effect on T3 concentration, that of TSH in serum was increased approximately 2. Significant positive correlations have been observed between TCDD-induced decreases in plasma T4 concentration and concomitant induction of hepatic UGT1, indicating that TCDD functions predominantly at an extrathyroidal level Schuur et al.
Further evidence for a mechanism of action that does not directly involve the thyroid gland was obtained in the long-term bioassay in which male and female Sprague-Dawley rats were given TCDD at doses of 0. Indications of reduced T4 protein binding decreased ratio of total: Various hydroxylated metabolites of PCBs have been shown to competitively displace T4 binding to human transthyretin but not to T4-binding globulin Lans et al.
Four of seven rats at the highest dose died, and decreased body-weight gain was seen at the three higher doses. Treatment had no effect on the weight gain of dams during gestation, on litter size or on pup survival or growth during lactation. No sex-specific differences were seen with respect to enzyme induction Seo et al. Characteristic symptoms of vitamin A deficiency have been observed in experimental animals and wildlife species after exposure to TCDD and various coplanar chemicals.
The mechanism of action appears to be persistent impairment of the ability of liver stellate cells to store vitamin A due to inhibition of lecithin: The initial kinetic effects after exposure to TCDD involve increased mobilization of vitamin A from hepatic storage sites, probably by retinal ester hydrolysis Kelley et al.