Recommended core outcome instruments for health-related quality of life, long-term control and itch intensity in atopic eczema trials: results of the HOME VII consensus meeting.

BACKGROUND: The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema (AE) clinical trials. Previous consensus meetings have agreed on preferred instruments for clinician-reported signs (Eczema Area and Severity Index, EASI) and patient-reported symptoms (Patient-Oriented Eczema Measure, POEM). This paper reports consensus decisions from the HOME VII meeting. OBJECTIVES: To complete the core outcome set for AE by agreeing on core outcome instruments for the domains of quality of life (QoL), long-term control and itch intensity. METHODS: A face-to-face consensus meeting was held in Tokyo, Japan (8-10 April 2019) including 75 participants (49 healthcare professionals/methodologists, 14 patients, 12 industry representatives) from 16 countries. Consensus decisions were made by presentations of evidence, followed by whole and small group discussions and anonymous voting using predefined consensus rules. RESULTS: It was agreed by consensus that QoL should be measured using the Dermatology Life Quality Index (DLQI) for adults, the Children's Dermatology Life Quality Index (CDLQI) for children and the Infant's Dermatology Quality of Life Index (IDQoL) for infants. For long-term control, the Recap of Atopic Eczema (RECAP) instrument or the Atopic Dermatitis Control Test (ADCT) should be used. Consensus was not reached over the frequency of data collection for long-term control. The peak itch numerical rating scale (NRS)-11 past 24 h was recommended as an additional instrument for the symptom domain in trials of older children and adults. Agreement was reached that all core outcome instruments should be captured at baseline and at the time of primary outcome assessment as a minimum. CONCLUSIONS: For now, the core outcome set for clinical trials in AE is complete. The specified domains and instruments should be used in all new clinical trials and systematic reviews of eczema treatments.

Recommended core outcome instruments for health-related quality of life, long-term control and itch intensity in atopic eczema trials: results of the HOME VII consensus meeting.

BACKGROUND: The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema clinical trials. Previous consensus meetings have agreed upon preferred instruments for clinician-reported signs (Eczema Area and Severity Index - EASI) and patient-reported symptoms (Patient-Oriented Eczema Measure - POEM). This paper reports consensus decisions from the HOME VII meeting. OBJECTIVE: To complete the core outcome set for atopic eczema by agreeing upon core outcome instruments for the domains of quality of life, long-term control and itch intensity. METHODS: Face-to-face consensus meeting held in Tokyo, Japan (8th to 10th April, 2019) including 74 participants (47 healthcare professionals/methodologists, 14 patients, 13 industry representatives), from 16 countries. Consensus decisions were made by presentations of evidence, followed by whole and small group discussions and anonymous voting using pre-defined consensus rules. RESULTS: It was agreed by consensus that quality of life should be measured using the Dermatology Life Quality Index (DLQI) for adults, the Children's Dermatology Life Quality Index (CDLQI) for children, and the Infant's Dermatology Quality of Life Index (IDQoL) for infants. For long-term control, the Recap of Atopic Eczema (RECAP) instrument or the Atopic Dermatitis Control Test (ADCT) should be used. Consensus was not reached over the frequency of data collection for long-term control. The peak itch numerical rating scale(NRS)-11 past 24 hours was recommended as an additional instrument for the symptom domain in trials of older children and adults. Agreement was reached that all core outcome instruments should be captured at baseline and at the time of primary outcome assessment as a minimum. CONCLUSIONS: For now, the core outcome set for clinical trials in atopic eczema is complete. The specified domains and instruments should be used in all new clinical trials and systematic reviews of eczema treatments.

Development and initial testing of a new instrument to measure the experience of eczema control in adults and children: Recap of atopic eczema (RECAP).

BACKGROUND: Eczema control has been identified as an important outcome by key stakeholders in eczema research (including patients, carers, healthcare professionals and researchers) but no validated instruments for the domain have been identified. OBJECTIVES: To develop a measurement instrument to capture a patient's perspective of eczema control that is suitable for use in eczema clinical trials. METHODS: Best practice for the development of a patient-reported outcome was followed. A mixed-methods approach was used to develop and refine a conceptual framework, generate, refine and select items and to test the distribution and construct validity of the final scale. The mixed-methods approach involved expert panel meetings (including patient representatives, healthcare professionals and methodologists), and data collection using a focus group, cognitive interviews and an online survey with people with eczema and caregivers. Multivariable linear regression was used in the item selection process. RESULTS: Fourteen expert panel members co-produced the instrument, with input from people with eczema and caregivers via a focus group (n = 6), cognitive interviews (n = 13) and an online survey (n = 330). The resulting instrument, Recap of atopic eczema (RECAP), is a seven-item questionnaire that captures eczema control via self or caregiver report. The development process aimed to ensure good content validity and feasibility. Initial testing suggested no floor or ceiling effects and good construct validity. Hypothesized correlation with the Patient-Oriented Eczema Measure was confirmed [r(258) = 0·83, P < 0·001]. CONCLUSIONS: RECAP has the potential to improve reporting of eczema control in research and clinical practice. Further exploration of measurement properties is required. Linked Comment: Pattinson and Bundy. Br J Dermatol 2020; 183:418-419. What's already known about this topic? Eczema control has been identified as an important outcome by key stakeholders in eczema research (including patients, carers, healthcare professionals and researchers). Qualitative studies suggest eczema control is a multifaceted and individual experience and no instrument has been identified that captures eczema control in this way. What does this study add? We have developed Recap of atopic eczema (RECAP), a seven-item questionnaire to capture the experience of eczema control in all ages and eczema severities; there are two versions: a self-reported version for adults and older children with eczema, and a caregiver-reported version for younger children with eczema. Designed with input from people with eczema, caregivers and healthcare professionals to ensure good content validity. Initial testing of score distributions and construct validity suggests good measurement properties. What are the clinical implications of the work? The RECAP instrument is appropriate and feasible for measuring eczema control in clinical trials and may also be useful in routine practice.

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12-14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon.

Barriers to maternal workforce participation and relationship between paid work and health.

BACKGROUND: Families of children with disabilities experience extra financial strains, and mothers are frequently unable to participate in paid work because of caregiving obligations. METHODS: A mailed survey and follow-up phone calls were used to gather data about mother's health, workforce participation and barriers to inclusion in the workplace (n = 152). Verbatim reports of issues that hindered workforce participation were analysed qualitatively to derive themes. Maternal health-related quality of life (HRQoL) was measured using the Short Form Health Survey Version 2 (SF-36v2). Norm-based conversions were used to compare HRQoL between working and non-working mothers and to compare to population norms. RESULTS: Eighty-two per cent of mothers in the sample wanted and needed to work for pay but indicated over 300 issues that prevent their work participation. Data analysis revealed 26 common issues which prevent work participation. These issues fit into three main categories: mother-related reasons (28%), child-related reasons (29%) and service limitations (43%). Mothers who worked (n = 83) reported significantly better HRQoL than mothers who did not work (n = 69) on five of the eight SF-36v2 dimensions and overall mental health. CONCLUSIONS: Compared to other working Australians, mothers in this study had higher education yet reported poorer health, lower family income and lower workforce participation. Respondents reported that service system limitations were the main barriers to participation in the paid workforce. Investigation of service changes such as increased respite care, availability of outside hours school care, improved professional competency and family-centred services is recommended in order to improve maternal participation in paid work.

Development of the Child's Challenging Behaviour Scale (CCBS) for mothers of school-aged children with disabilities.

BACKGROUND: Caring for a child with a disability can be especially difficult when the child exhibits challenging behaviours. Childhood disability often calls for the mother to be conscientious, capable and organized to meet the child's health and developmental needs. Mothers are known to feel particularly stressed when their child also behaves in ways that are difficult to manage. In these circumstances maternal mental health may be compromised and mothers therefore need more support. The Child's Challenging Behaviour Scale (CCBS) is an 11-item scale that measures a mother's report of challenging behaviours exhibited by their child with disability, that are associated with compromised maternal mental health and caregiving difficulties. This paper describes the initial development and psychometric evaluation of the CCBS. METHODS: A mixed methodology instrument design model was used to develop the CCBS. A qualitative study generated items, and quantitative data were collected from 152 mothers of a child with a disability. RESULTS: The CCBS showed excellent internal consistency (Cronbach's alpha = 0.89) and factor analysis supported its unidimensionality. Construct validity was supported by correlations with the PedsQL Psychosocial Health Summary Score (rho =-0.51) and cooperation taking medication (rho = 0.40). There were significant differences in CCBS scores between groups of children with and without either autism or psychiatric conditions. The CCBS showed moderate correlations with self-reported health status; the mother's sense of empowerment (rho =-0.44); and family cohesion (rho =-0.30). Mothers with a mental health condition recorded significantly higher CCBS scores. CONCLUSIONS: The CCBS is a brief, psychometrically sound instrument that provides clinicians with a new tool that measures a mother's rating of their child's behaviours that are challenging and associated with reduced maternal well-being. The CCBS assists professionals to identify mothers and family situations who may be in need of more support and interventions.

Development of the Assistance to Participate Scale (APS) for children's play and leisure activities.

AIM: This paper describes the development and psychometric evaluation of the Assistance to Participate Scale (APS). The APS measures the assistance that a school-aged child with a disability requires to participate in play and leisure activities from the primary carer's perspective. METHOD: Mixed methodology using an instrument design model was used to complete two studies. First, a qualitative research design was used to generate items and scoring criteria for the APS. Second, a quantitative study evaluated the instrument using data collected from 152 mothers with children aged 5-18 years. Statistical analysis assessed the underlying structure, internal consistency and construct validity of the APS. RESULTS: Exploratory factor analysis revealed two correlated components, reflecting home-based and community-based play activities. Both subscales and the total APS scale showed good internal consistency. The APS correlated as predicted with individual domains and overall scores for other validated measures (Pediatric Evaluation of Disability Inventory caregiver scales and Pediatric Quality of Life Inventory) with correlations ranging from rho = 0.42 to rho = 0.77. The APS was able to discriminate between groups of children based on type of schooling (regular or segregated), need for equipment/assistive devices, frequency of lifting and disability. CONCLUSIONS: The APS provides professionals with a brief psychometrically sound tool that measures the amount of caregiver assistance provided to a child with a disability to participate in play and recreation. The APS may be used as an outcome measure and to evaluate and predict the amount and type of additional assistance families need to facilitate their child's participation in an important aspect of the child's daily life and development: play and recreation.

Trends and differential use of assistive technology devices: United States, 1994.

OBJECTIVE: This report presents data on annual estimates of the prevalence of use of selected assistive technology devices for vision, hearing, mobility, and orthopedic impairments, including missing limbs. Also presented are statistics on trends in the prevalence of use of selected mobility assistive technology devices for the years 1980, 1990, and 1994. METHODS: The data used for this report are from the 1994 National Health Interview Survey on Disability (NHIS-D), Phase I, which was co-sponsored by a consortium of U.S. Federal agencies and private foundations. All estimates are based on data from the NHIS-D, Phase I, which represent the civilian, noninstitutional population of the United States. RESULTS: An estimated 7.4 million persons in the U.S. household population used assistive technology devices for mobility impairments, 4.6 million for orthopedic impairments (including missing limbs), 4.5 million for hearing impairments (not including impairments fully compensated by hearing aids), and 0.5 million for vision impairments. Use of any mobility device for all ages had the highest prevalence rate at 28.5 per 1,000 persons. There was a positive correlation between an increase in age and the increase in the prevalence rate of device usage; for example, of persons in the age group 65 years and over, the rate of mobility, hearing, and vision device usage was more than 4 times the rate for the total population. CONCLUSION: Assistive technology use has increased because of population size, age composition changes, and a change in the rate of use. Medical and technological advances along with public policy initiatives have also contributed to increased usage.

Mutagenic potential of binary and complex mixtures using different enzyme induction systems.

A series of experiments was conducted to investigate the mutagenic potential of binary and complex mixtures in the presence and absence of inducible liver enzyme systems prepared with several different chemical inducers. Liver homogenate (S9, or 9000 x g supernatant) fractions were obtained from Sprague-Dawley rats induced with either Aroclor 1254 (AR), phenobarbital (PB), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or corn oil (UI). the mutagenic potential of test samples was measured with Salmonella typhimurium strain TA98 using each of the various S9 fractions. Test samples included benzo[a]pyrene (BaP), pentachlorophenol (PCP), a binary mixture of BaP and PCP, two five-component mixtures, a methylene chloride extract of wood preserving waste-amended soil, and a methanol extract of coal gasification waste. At a dose of 25 micrograms/plate, BaP produced 55, 83, 217, and 161 net revertants per plate with UI-, PB-, AR-, and TCDD-induced S9, respectively. The complex mixture extracted from the wood preserving waste-amended soil induced approximately equal responses with all four S9 mixes. At a dose of 250 micrograms/plate, the methanol extract of a coal gasification waste produced 56 net revertants using the uninduced S9; however, when Ar- and TCDD-induced S9 was used, 129 and 67 net revertants were observed, respectively. These data demonstrate the relative importance of the various induced cytochrome P-450 isozymes for the metabolism of mutagenic chemicals and complex mixtures.

Relative sensitivities of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Cyp1a-1 and Cyp1a-2 gene expression and immunotoxicity in female B6C3F1 mice.

Improvements in risk assessment require better linkage of exposure to response by the determination of target tissue dose. The relative sensitivity of several responses in female B6C3F1 mice was compared on the basis of administered and target tissue dose spanning 3 orders of magnitude. Twenty-four hours after administration, [3H]TCDD was detected in the heart, spleen, kidney, uterus, thymus, lung, and liver, and the highest concentrations were noted in the liver, uterus, and lung. At doses from 5 to 25 ng/kg, hepatic [3H]TCDD levels associated with the cytosolic and nuclear subcellular fractions increased from 12 to 62% of the total liver levels and then decreased at higher doses. At the two lowest doses used in the enzyme induction study, 5 and 10 ng/kg, the levels of specifically bound nuclear Ah receptor complex liganded with [3H]TCDD were 2.3 and 2.5 fmol/mg protein. Slightly higher levels of nuclear Ah receptor complex were observed at doses between 25 and 100 ng/kg (i.e., 3.6 to 4.2 fmol/mg protein) and a steep dose-dependent increase in nuclear Ah receptor levels was noted at doses of 500, 1000, and 5000 ng/kg (8.0, 39.3, and 92.8 fmol/mg protein, respectively). The dose-dependent effects of [3H]TCDD on hepatic Cyp1a-1 and Cyp1a-2 mRNA levels, ethoxyresorufin O-deethylase (EROD) activity, and the splenic antibody plaque-forming cell (PFC) response to sheep red blood cells were also determined; the latter response was determined 9 days after administration of TCDD. Statistically significant induction of hepatic Cyp1a-1 was observed at lower doses (25 ng/kg) than any other marker, followed by induction of EROD and PFCs expressed per spleen or per 10(6) cells which was observed at 100 ng TCDD/kg and at higher doses. Cyp1a-2 was elevated significantly relative to control at doses > or = 1000 ng/kg. The ED50 value for PFCs/10(6) cells was the lowest of the variables analyzed and was not statistically significantly different from control (91 +/- 92 ng/kg). A 50% increase in Cyp1a-2 and Cyp1a-1 mRNA levels was observed at doses of 736 +/- 132 and 1630 +/- 431 ng/kg, respectively. Due to variability in response in PFCs/spleen and the submaximal induction of EROD activity, ED50 values could not be calculated for these responses. The analyses indicate that the immunosuppressive response (when normalized for the number of spleen cells) may be depressed by administered doses as low as 90 ng TCDD/kg body weight. A 50% increase in Cyp1a-1 or Cyp1a-2 was observed at higher administered doses (1630 or 736 ng/kg, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunosuppressive effects of highly chlorinated biphenyls and diphenyl ethers on T-cell dependent and independent antigens in mice.

The dose-dependent effects of 2,2',3,3',4,4',5,5',6-nonachlorobiphenyl (nonaCB), 2,2',3,3',4,4',5,6,6'-nonaCB, 2,2',3,3',4,5,5',6,6'-nonaCB and decaCB on the suppression of the splenic plaque-forming cell (PFC) response to the T-cell-dependent antigen, sheep red blood cells (SRBCs) and the T-cell-independent antigen, trinitrophenyl-lipopolysaccharide (TNP-LPS), were determined in genetically inbred mice. In addition, the induction of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity was also measured. The highly chlorinated biphenyls suppressed the splenic PFC response to SRBCs in C57BL/6 and DBA/2 mice and were relatively more active in the former strain. The C57BL/6 mice are more responsive to aryl hydrocarbon (Ah) receptor agonists than DBA/2 mice and these data support a possible role for the Ah receptor in mediating this response. However, previous studies with polychlorinated biphenyls (PCBs) indicate that congeners with 3 or 4 ortho-chloro substituents are inactive as Ah receptor agonists and this was consistent with the minimal induction of hepatic microsomal EROD activity by the highly chlorinated biphenyls in both strains of mice. Thus, the results suggest that the inhibition of the splenic PFC response to SRBCs observed in this study was primarily an Ah receptor-independent response. Some of the highly chlorinated diphyenyl ethers namely decachlorodiphenyl ether and 2,2',3,3',4,4',5,6,6'-nonachlorodiphenyl ether, inhibited the antigenic response to TNP-LPS in C57 BL/6 mice. The results indicate that the suppression of the TNP-LPS-mediated immune response may be a more reliable indicator of the Ah receptor-dependent immunotoxicity of halogenated hydrocarbons.

Ophthalmic examination among adults with diagnosed diabetes mellitus.

OBJECTIVE: To assess whether adults with diagnosed diabetes in the United States are receiving recommended eye examinations for detection of diabetic retinopathy and what factors are associated with receiving them. DESIGN, SETTING, AND PARTICIPANTS: The design was a cross-sectional survey of the civilian, noninstitutionalized US population 18 years of age or older, based on the 1989 National Health Interview Survey. A multistage probability sampling strategy was used to identify a representative sample of 84,572 persons. A questionnaire on diabetes was administered to all subjects with diagnosed diabetes (n = 2405). MAIN OUTCOME MEASURE: A dilated eye examination in the past year. MAIN RESULTS: Of all adults with diagnosed diabetes in the United States, only 49% had a dilated eye examination in the past year. This included 57% of people with insulin-dependent diabetes mellitus (IDDM), 55% with insulin-treated non-insulin-dependent diabetes mellitus (NIDDM), and 44% with NIDDM not treated with insulin. Even among diabetics at high risk of vision loss because of retinopathy or long duration of diabetes, the proportion with a dilated eye examination was only 61% and 57%, respectively. By logistic regression, the probability of a dilated eye examination among persons with NIDDM increased with older age, higher socioeconomic status, and having attended a diabetes education class. The probability of a dilated eye examination was not independently related to race, duration of diabetes, frequency of physician visits for diabetes, or health insurance. CONCLUSIONS: About half of adults with diabetes in the United States are not receiving timely and recommended eye care to detect and treat retinopathy. Widespread interventions, including patient and professional education, are needed to ensure that diabetic patients who are not receiving appropriate eye care have an annual dilated eye examination to detect retinopathy and prevent vision loss.

Self-monitoring of blood glucose by adults with diabetes in the United States population.

OBJECTIVE: To evaluate self-monitoring of blood glucose, which is considered an important practice for patients with diabetes. However, little is known about the frequency or determinants of this technique. RESEARCH DESIGN AND METHODS: A detailed questionnaire on diabetes was administered to a representative sample of 2405 diabetic subjects > or = 18 yr of age in the U.S. population in the 1989 National Health Interview Survey. RESULTS: Among subjects with IDDM, 40% monitored their blood glucose at least 1 time/day. Among subjects with NIDDM treated with insulin, 26% monitored at least 1 time/day and among NIDDM subjects not treated with insulin, the percentage was 5%. When stratified by age, little difference was observed between IDDM subjects and insulin-treated NIDDM subjects in the percentage testing at least 1 time/day. By multivariate analysis, age and insulin use were the major determinants of whether diabetic subjects tested their blood glucose. Race and education were also independently related to self-monitoring of blood glucose. Blacks were 60% less likely to test their blood glucose at least 1 time/day compared with non-Hispanic whites and Mexican Americans. Those with college education were 80% more likely to test their blood glucose compared with those with lower education levels. Having had a patient education class in diabetes management and frequent physician visits for diabetes care were positively related to self-testing. Self-monitoring was not related to higher income or having health insurance. CONCLUSIONS: A large proportion of patients with diabetes do not test their blood glucose. Financial barriers associated with income and health insurance do not appear to impede the practice of self-monitoring. Because of the importance of blood glucose control in the prevention of diabetes complications and the role of self-monitoring in achieving blood glucose control, it may be prudent for physicians and their patients to make greater use of this technique. Special attention should be directed to the subgroups of patients (blacks, patients not treated with insulin, those with less education, and those with no education in diabetes) in which the frequency of self-monitoring is particularly low.

Immunosuppressive and monooxygenase induction activities of highly chlorinated diphenyl ether congeners in C57BL/6 and DBA/2 mice.

The dose-response effects of 2,2',3,3',4,5,5',6,6'-2,2',3,3',4,4',5,6,6'- and 2,2',3,3',4,4',5,5',6- nonachlorodiphenyl ether (non-aCDE) and decachlorodiphenyl ether (decaCDE) on the splenic plaque-forming cell (PFC) response to sheep red blood cells (SRBCs) and the induction of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity was determined in aryl hydrocarbon (Ah)-responsive C57BL/6 and less Ah-responsive DBA/2 mice. All the congeners exhibited immunotoxicity at doses between 2.5 and 10 mumol/kg in C57BL/6 mice whereas in DBA/2 mice doses > or = 25 mumol/kg were required to cause inhibition of the PFC response to SRBCs. The results also showed that the nonaCDE isomers and decaCDE were more active as inducers of hepatic EROD activity in C57BL/6 than DBA/2 mice; however, there was not a correlation between the induced EROD activity and the CYP1A1 and CYP1A2 mRNA levels in the C57BL/6 mice. These data suggested that the immunotoxicity of these compounds was mediated through the Ah receptor. However, the results showed that the immunotoxicity of the nonaCDE isomers and decaCDE was unexpectedly high compared to that of lower chlorinated diphenyl ethers and there were no apparent structure-activity relationships among the higher chlorinated congeners. This suggests that some of the immunosuppressive effects observed for the nonaCDE isomers and decaCDE may be Ah receptor-independent.

Teratogenicity and immunotoxicity of 3,3',4,4',5-pentachlorobiphenyl in C57BL/6 mice.

Administration of 3,3',4,4',5-pentachlorobiphenyl (pentaCB) to female C57BL/6 mice at doses from 130.5 to 522 micrograms/kg body weight resulted in the dose-dependent formation of fetal cleft palate and hydronephrosis. The estimated relative potency of 3,3',4,4',5-pentaCB compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was in the range of < 0.07-0.04. The immunotoxicity of 3,3',4,4',5-pentaCB and two structurally-related congeners, 3,3',4,4'-tetraCB and 3,3',4,4',5,5'-hexaCB, was investigated in male C57BL/6 mice by determining their suppression of the splenic plaque-forming cell response to sheep red blood cells. The potencies of these compounds relative to TCDD were determined from the ratios of their corresponding ED50 values and were 0.77-0.55 (3,3',4,4',5-pentaCB), 1.1-0.29 (3,3',4,4',5,5'-hexaCB) and 0.14-0.03 (3,3',4,4'-tetraCB). These results demonstrate that the immunosuppressive activities of the PCB congeners relative to TCDD were much higher than observed for many other TCDD-like responses in mice and other laboratory animals.

The effect of 6-nitro-1,3,8-trichlorodibenzofuran as a partial estrogen in the female rat uterus.

Administration of 6-nitro-1,3,8-trichlorodibenzofuran (6-NCDF) caused a dose- and time-dependent increase in uterine wet weight and cytosolic and nuclear estrogen receptor (ER) and progesterone receptor (PR) levels in immature female Sprague-Dawley rats. These estrogenic effects persisted for up to 96 or 144 hr after initial administration of 6-NCDF and could be observed at a dose as low as 2 mumol/kg. In contrast, 6-NCDF (25 mumol/kg) did not increase rat uterine peroxidase activity or epidermal growth factor (EGF) receptor binding activity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), which exhibits a broad spectrum of antiestrogenic effects in the female rat uterus, inhibited the 17 beta-estradiol-induced increase in uterine wet weights, cytosolic and nuclear ER and PR levels, peroxidase activity, and EGF receptor binding activity. In contrast, 2,3,7,8-TCDD inhibited the uterotropic effects caused by 6-NCDF but did not affect the 6-NCDF-induced uterine ER and PR levels. 6-NCDF is a weak inducer of hepatic microsomal ethoxyresorufin O-deethylase activity and competitively binds to the aryl hydrocarbon (Ah) receptor but not the PR or ER. Thus both 6-NCDF and 2,3,7,8-TCDD, two ligands which bind to the Ah receptor, exhibit both partial estrogenic and antiestrogenic properties and serve as useful models for delineating the complex biochemical interactions between the ER and Ah receptor signal transduction pathways.

Immunosuppressive and monooxygenase induction activities of polychlorinated diphenyl ether congeners in C57BL/6N mice: quantitative structure-activity relationships.

The dose-response effects of several polychlorinated diphenyl ether (polyCDE) congeners on the inhibition of the splenic plaque-forming cell (PFC) response to sheep red blood cell antigen and the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities were determined in male C57BL/6 mice. The immunotoxic potencies for the polyCDE congeners (ED50 values for the suppression of PFCs/spleen and PFCs/10(6) cells) followed the order 2,3,3',4,4',5-hexaCDE (0.5 and 2.2 mumols/kg) greater than 3,3',4,4',5-pentaCDE (8.8 and 5.1 mumols/kg) greater than 2,3',4,4',5-pentaCDE (21.8 and 14.2 mumols/kg) greater than 3,3',4,4'-tetraCDE (50.6 and 28.7 mumols/kg) greater than 2,2',4,4',5,5'-hexaCDE (81.2 and 56.5 mumols/kg) greater than 2,2',4,5,5'-pentaCDE (258 and 228 mumols/kg) greater than 2,2',4,4',5,6'-hexaCDE (greater than 400 mumols/kg for both responses). The potencies of the polyCDE congeners as inducers of hepatic microsomal AHH and EROD activities were similar to their immunotoxicities and only one compound, namely, 2,3',4,4',5,5'-hexaCDE, did not cause dose-response immunosuppressive effects in the mice. The structure-activity relationships for the polyCDEs exhibited both differences and similarities. For example, the coplanar 3,3',4,4'-tetraCDE and 3,3',4,4',5-pentaCDE congeners were less immunotoxic than their monoortho 2,3',4,4',5-pentaCDE and 2,3,3',4,4',5-hexaCDE analogs, respectively, and similar results were also observed for their enzyme induction potencies. For the corresponding polychlorinated biphenyls (PCB) congeners the coplanar compounds were significantly more active than their monoortho analogs. In addition, two diortho-substituted compounds, namely, 2,2',4,5,5'-pentaCDE and 2,2',4,4',5,5'-hexaCDE, were also immunotoxic at a dose of 400 mumols/kg whereas, their PCB analogs were inactive. These studies clearly demonstrate that for the polyCDE congeners, increasing ortho-chloro substitution is less effective in reducing the activity of these congeners compared to the well-recognized ortho effects reported for the PCBs. The differences in the structure-activity relationships between polyCDEs and PCBs are related to the ether bridge in the polyCDEs in which the resultant increased bond length between the two phenyl rings thereby diminishes the effects of ortho substituents on the biochemical and toxic potencies of these compounds.