Assessing Regulatory Impact Analyses: The Failure of Agencies to Comply With Executive Order 12,866

None.Environment, Health and Safety, Regulatory Reform

Assessing the Quality of Regulatory Impact Analyses

This study provides the most comprehensive evaluation of the quality of recent economic analyses that agencies conduct before finalizing major regulations. We construct a new dataset that includes analyses of forty-eight major health, safety, and environmental regulations from mid-1996 to mid-1999. This dataset provides detailed information on a variety of issues, including an agency's treatment of benefits, costs, net benefits, discounting, and uncertainty. We use this dataset to assess the quality of recent economic analyses and to determine the extent to which they are consistent with President Clinton's Executive Order 12866 and the benefit-cost guidelines issued by the Office of Management and Budget (OMB). We find that economic analyses prepared by regulatory agencies typically do not provide enough information to make decisions that will maximize the efficiency or effectiveness of a rule. Agencies quantified net benefits for only 29 percent of the rules. Agencies failed to discuss alternatives in 27 percent of the rules and quantified costs and benefits of alternatives in only 31 percent of the rules. Our findings strongly suggest that agencies generally failed to comply with the executive order and adhere to the OMB guidelines. We offer specific suggestions for improving the quality of analysis and the transparency of the regulatory process, including writing clear executive summaries, making analyses available on the Internet, providing more careful consideration of alternatives to a regulation, and estimating net benefits of a regulation when data on costs and benefits are provided.

Infant temperament predicts life span in female rats that develop spontaneous tumors

Abstract In a recent study, we found that male rats that minimally explored a novel environment as infants died significantly faster than their more exploratory brothers. At death, these males had various complex pathologies, precluding identification of specific hormonal mechanisms underlying adult disease progression and mortality. To minimize the variance of disease processes at the end of life, we conducted a longitudinal study with female Sprague-Dawley rats prone to high rates of spontaneous mammary and pituitary tumors. For females that developed either mammary or pituitary tumors, those that had been neophobic (least exploratory) as infants died approximately 6 months earlier than their neophilic (most exploratory) sisters. In the case of mammary tumors, both benign and malignant, neophobic females developed palpable tumors earlier than neophilic females, whereas the interval between first palpation and death was the same for all females, indicating psychosocial regulation of early rather than later stages of the disease. Neophobic females' ovarian function aged more rapidly than their neophilic sisters. Concomitantly, they had lower corticosterone responses to restraint in late adulthood, ruling out high estrogen or corticosterone levels during senescence as causal factors in their accelerated mortality. During puberty, when mammary tissue is proliferating and differentiating, neophobic females experienced more irregular cycles with prolonged "luteal" phases, suggesting a role for prolactin, prolonged progesterone and fewer estrogen surges during this sensitive period for mammary tumor risk. Thus, we identified prolactin, estrogen, progesterone and possibly corticosterone dynamics as candidates for neuroendocrine mechanisms linking infant temperament with onset of adult neoplastic disease. © 2006 Elsevier Inc. All rights reserved. Keywords: Temperament; Personality; Mammary tumors; Pituitary tumors; Reproductive cycles; Glucocorticoid dynamics; Longevity; Sibling differences Stable behavioral traits (e.g. temperament, personalities) are often associated with specific hormonal profiles (e.g. gonadal and/or adrenal function). Given the stability of certain behavioral/endocrine traits and the known costs and benefits of certain hormonal profiles Given the well-established bidirectional influence of ovarian steroids, prolactin and glucocorticoids on behavior and tumor cells, we focused on individual differences in the development of spontaneous tumors in a rodent model. Hormones have a wide array of influences on tumor development, with different effects depending on the kind of tumor, the stage of tumor development and the timing and duration of hormonal exposure. Tumor initiation may be regulated by both ovarian steroids and glucocorticoids. Dexamethasone decreases apoptosis in mammary cancer cells in vitro, increasing risk of spontaneous mutations and, if operable in vivo, accelerating spontaneous tumor Hormones and Behavior 50 (2006) initiation In a recent life span study of Sprague-Dawley rat brothers, we found that those reluctant to explore a new environment in infancy (i.e. neophobic) sustained that temperament into adulthood, had elevated corticosterone responses to novelty in adulthood and died earlier than their more exploratory brothers Much of the above work on mammary tumors has been done in vitro or with induced tumors or xenographs. Here, we tested the hypothesis that a neophobic temperament in infant females increases mortality rate as it did in males and extended the hypothesis to the onset and progression of spontaneous mammary tumor formation. We compared the following processes for females identified as neophobic or neophilic during infancy: frequency of spontaneous mammary and pituitary tumors, age when mammary tumors were first palpable, natural life span of females with tumors, ovarian function from late puberty to reproductive senescence and glucocorticoid responses during senescence. To minimize genetic variance among temperament types, we studied within family differences. In summary, we address the following questions: (1) is exploration of a novel environment a stable trait over the female life span? (2) Do infant female behavioral responses predict mortality rates in rats afflicted with spontaneous mammary or pituitary neoplasias? (3) Are ovarian function and/or glucocorticoid dynamics associated with infant temperament, providing potential mechanisms for differential disease progression and/or mortality rates among temperament types? If Sprague-Dawley sisters are like their brothers, we expect those with a neophobic temperament to have elevated glucocorticoid responses to novelty Methods Overall protocol Eighty-one female pups were selected from 14 independently bred SpragueDawley litters (parents from Charles River Laboratories, Wilmington, Massachusetts; selection criteria for exploratory temperament described below). Six sisters were selected for within-family comparisons because of known between-family differences in behavior, corticosterone responses and life span (Cavigelli and McClintock, unpublished data). Females lived throughout their lives in solid bottom plastic cages (43.5 × 23.5 × 20.5 cm) on a 14L:10D lighting schedule (lights on at 20:00 h) with food and water ad libitum. Cages were cleaned twice a week. Females were not allowed to breed. Until 22 days of age, females lived with their mother and littermates. Their mothers and brothers were then removed, and they continued living with their sisters until 27 days. As part of another study on peripubertal social experiences, housing conditions were manipulated during 28-46 days of age; 1/3 lived with two sisters, 1/3 with two unfamiliar females and 1/3 alone. This manipulation did not affect variables examined in this report and is therefore not discussed further. At 47 days of age, all females were housed in groups of 3 sisters per cage for the rest of their lives. Each trio included one low exploration, one intermediate exploration and one high exploration sister (based on testing at 20 days described below; trios were counterbalanced for peripubertal social experience). Daily vaginal cytology samples collected from each female from late-puberty through reproductive senescence were used to analyze ovarian cycle phase durations Temperament: behavioral response to a complex novel environment We measured rats' willingness to explore a complex novel environment at 20 days of age and again at 11 months of age. The first test was conducted just prior to typical weaning and moving above ground in the field For behavioral coding, nine square areas (940 or 1655 cm 2 for infant or adult arena) were defined by a 3× 3 grid. Exploration in the arena was quantified by the number of times a rat walked from one of the areas to an adjacent area (locomotion score). In a confirmatory factor analysis, this movement was associated with other exploratory behaviors in infancy, including sniffing and touching the objects, and in late adulthood with sniffing and climbing on them. It was not associated with escaperelated behavior such as inspecting or rearing up on the walls of the enclosure. Thus, the locomotion score in this arena probably reflects exploration and not high levels of undirected motor activity. Selection criteria Locomotion scores (our index of exploration) varied within and among litters (within litter ranges for the extremes: 0-34 vs. 0-76 squares entered). Females were categorized and selected based on their performance relative to the mean performance of all females within their family. The two most active sisters were identified as 'neophilic', the two least active were identified as 'neophobic' and those with values closest to the family mean as 'intermediate'. These categories are slightly different from those used in the previous study of males, in which we excluded the least active (i.e. nonresponding) males from each litter because they weighed less than their littermates. In this previous study, the male pups that showed intermediate levels of activity in the test arena were identified as 'neophobic' since the least exploratory were excluded. Pathology and life span Females were allowed to live their natural life span. Health of aging females was closely monitored by researchers and the institutional veterinarian. To preclude suffering, 47 of the 81 females were sacrificed when they displayed symptoms indicating that they were within 1 week of death Mammary tumors To determine age of mammary tumor detection, we used a comprehensive technique for repeatedly palpating all mammary tissue; three checkers could reliably detect mammary neoplasia as small as 3 mm in diameter. Regular checks began just prior to 10 months of age and were repeated every 2-3 weeks until death. We defined onset of tumor detection as the first date at which a growth was reliably palpable. Checkers were not informed as to which females had been palpated with tumors in the previous weeks. At necropsy, the ovoid mammary tumors were well encapsulated and easily excised. Mean (±SEM) mammary tumor size across all females was 78.4 ± 15.6 g, approximately 20% of the mean aged female body weight (i.e. approximately 400 g). Random samples revealed that they were histologically complex, with multiple tumor subtypes within a single solid tumor. Tumor diagnoses included malignant cancer (e.g. in situ ductal carcinoma (comedo and cribiform), invasive ductal carcinoma and carcinosarcoma) as well as benign tumors (e.g. fibroadenoma, lactacting adenoma and papillary cystadenoma). Histological diagnosis was validated by concordance of two surgical pathologists specializing in breast cancer pathology in the Department of Pathology at the University of Chicago. Pituitary tumors Necropsies were performed to determine presence of a pituitary tumor and to excise mammary tumors. Pituitary tumors were defined by pituitary gland enlargement (0.263 ± 0.017 g, as compared to normal range of pituitary gland: 0.009-0.074 g), extensive vasculature and confirmed histologically by concordance of the two surgical pathologists. Other gross morphological abnormalities were also noted indicating disease processes at the time of death (i.e. enlarged or abnormally small organs and other tumors). Hormonal function Ovarian cycles from puberty through reproductive senescence Ovarian cycles were monitored daily from 55 to 450 days to measure cycle length and estimate the number of days each female spent in estrogenized or nonestrogenized "luteal" phases of each cycle (e.g. proestrus and estrus with cornified vaginal epithelium cells and no leukocytes followed by metestrus and diestrus with leukocytes and few cornified cells). To assess ovarian cycles, cells of the vaginal wall were collected by saline lavage during the middle of the dark (active) period. Samples were quantified according to the relative proportion of three cell types: cornified epithelial cells, nucleated epithelial cells and leukocytes. Rats were in the post-ovulatory ('luteal') phase when leukocytes represented more than 20% of the cells in a sample for two or more consecutive days Given potential sensitive periods for sex steroid influences on mammary tumorigenesis and progression At each age, we determined how many females were in one of four ovarian states: regular cycles, constant estrus, irregular cycles and persistent diestrus or anestrus (coding methods in Corticosterone response to restraint stressor at late middle age To determine if late adult corticosterone reactivity, following tumorigenesis, differed between neophobic and neophilic females, we collected repeated blood samples following brief physical restraint at 15 months of age. Restraint consisted of 30 min in a Plexiglas tube, which is considered a psychological stressor for these animals. Tube diameters were adjusted for individual female body weights, such that none was constricted. Blood sampling was performed at the end of the rats' active period (starting between 20:00 and 21:00 h). At this time, females were removed from their home cage in a pre-determined randomized order, carried to an adjacent room where blood sampling was conducted, placed into a restraint tube and bled within 4 min of home cage removal. After the first sample, the rats remained in the tube for 30 min, at which point a second sample was collected and the rats removed from the tube and placed in a clean solid-bottom plastic cage. Repeated samples were collected at 60, 90 and 150 min from the initial sample. The first sample was intended to capture unstimulated corticosterone concentrations. The 60-min sample, collected 30 min from the end of physical restraint, was timed to capture the near-maximal corticosterone response to this challenge. And the 150-min sample was collected to capture recovery levels-how quickly the corticosterone response is terminated and corticosterone removed from the system after a 30-min novelty. Females were processed on nine sequential evenings, with equal numbers of neophobic, intermediate and neophilic sisters bled each night and sampling time balanced across female temperaments. Blood was collected from the tip of the tail. Approximately 3 mm of the tail tip was removed with a scalpel blade and bleeding induced by tail palpation. Blood was collected into EDTA tubes (Microtainers from Becton Dickinson and Company) and kept on ice until centrifuged to collect plasma. Plasma was diluted (1:200 with assay kit diluent) and frozen at −80°C until assayed. Corticosterone was measured using a commercial radioimmunoassay kit (Rat and Mice Corticosterone kit, MP Biomedicals). All diluted samples were run in duplicate across nine assays. Sisters were included on the same assay. Intraassay and inter-assay variability for a low and high control were 9.8 and 8.7% and 13.3 and 12.7%. Consulting veterinarians concurred that cause of death in aging rats likely involves a complex interaction of multiple pathologies, and thus determining specific cause of death for all animals was beyond the scope of this study. To simplify analysis of the ongoing disease processes at the end of life and control for the two major types of neoplastic processes at the time of death, life span analyses were conducted within the two groups of females that had either mammary (N = 18) or pituitary tumors (N = 18) at death. Some of their sisters had both a pituitary and mammary tumors (N = 38), while others had rare types of pathology-e.g. invasive thoracic and/or abdominal cavity tumors (N = 5), cerebral hemorrhage (N =1), no detectable pathology at the time of death (N =1). To assess ovarian cycle patterns for each temperament, we compared relative representation in the four ovarian stages among neophobic, intermediate and neophilic females with χ 2 tests. To determine if baseline, reactivity or recovery levels of circulating corticosterone differed among the three temperament types, we used ANOVAs to compare corticosterone concentration at each sampling time, with post hoc paired t tests to compare neophobic and neophilic values. Because families had different overall corticosterone profiles, mean family corticosterone concentration at each time point was used as a covariate. Several females had died or were too ill for blood collection at 15 months; because temperament types were initially balanced within families, analyses of corticosterone data were limited to those sister trios in which all females were present for the blood collection (N = 54). Because estrous cycle profoundly affects corticosterone levels during the acrophase of the daily rhyth

MRI characterization of cobalt dichloride-N-acetyl cysteine (C4) contrast agent marker for prostate brachytherapy

Brachytherapy, a radiotherapy technique for treating prostate cancer, involves the implantation of numerous radioactive seeds into the prostate. While the implanted seeds can be easily identified on a CT image, distinguishing the prostate and surrounding soft tissues is not as straightforward. Magnetic Resonance Imaging (MRI) offers superior anatomical delineation, but the seeds appear as dark voids and are difficult to identify, thus creating a conundrum. Cobalt dichloride-N-acetylcysteine (C4) has previously been shown to be promising as an encapsulated contrast agent marker. We performed spin-lattice relaxation time (T1) and spin-spin relaxation time (T2) measurements of C4 solutions with varying cobalt dichloride concentrations to determine the corresponding relaxivities, r1 and r2. These relaxation parameters were investigated at different field strengths, temperatures and orientations. T1 measurements obtained at 1.5 T and 3.0 T, as well as at room and body temperature, showed that r1 is field-independent and temperatureindependent. Conversely, the T2 values at 3.0 T were shorter than at 1.5 T, while the T2 values at body temperature were slightly higher than at room temperature. By examining the relaxivities with the C4 vials aligned in three different planes, we found no orientation-dependence. With these relaxation characteristics, we aim to develop pulse sequences that will enhance the C4 signal against prostatic stroma. Ultimately, the use of C4 as a positive contrast agent marker will encourage the use of MRI to obtain an accurate representation of the radiation dose delivered to the prostate and surrounding normal anatomical structures

Cardioacceleration in alloparents in response to stimuli from prairie vole pups: The significance of thermoregulation

Autonomic responses, including changes in heart rate and respiratory sinus arrhythmia (RSA) can provide indications of emotional reactivity to social stimuli in mammals. We have previously reported that male prairie voles (Microtus ochrogaster) spontaneously care for unfamiliar infants, showing a robust and sustained increase in heart rate in the presence of a pup, thus providing an opportunity to examine the physiology of care-giving in reproductively naïve animals. However, the purpose of such heart rate increases has not been explained by previous efforts. In the present study, we first compared male and female prairie vole cardiac responses in the presence of a pup and found no evidence of sex differences in heart rate or RSA. Using male prairie voles, we then examined the characteristics of pups that were capable of eliciting physiological responses, including age of the pup and pup odors. As prairie vole pups increased in age they vocalized less and there was an associated decline in alloparental cardioacceleration. Exposure to pup-related odors induced cardioacceleration in adult males and this effect also diminished with increasing pup age. Finally, we were able to block the cardioacceleratory effect when the testing environment was warmed to a temperature of 36° C [versus ambient room temperature (approximately 22° C)]. These findings suggest that pup-induced cardioacceleration is a robust phenomenon across alloparental prairie voles of both sexes, and depends on multi-modal processing of different stimuli from the pups. Young pups require care-giving behavior, which appears to drive cardioacceleration in the alloparent. This study also supports the usefulness of autonomic measures in the evaluation of social experiences

Oxytocin promotes functional coupling between paraventricular nucleus and both sympathetic and parasympathetic cardioregulatory nuclei

The neuropeptide oxytocin (OXT) facilitates prosocial behavior and selective sociality. In the context of stress, OXT also can down-regulate hypothalamic–pituitary–adrenal (HPA) axis activity, leading to consideration of OXT as a potential treatment for many socioaffective disorders. However, the mechanisms through which administration of exogenous OXT modulates social behavior in stressful environmental contexts are not fully understood. Here, we investigate the hypothesis that autonomic pathways are components of the mechanisms through which OXT aids the recruitment of social resources in stressful contexts that may elicit mobilized behavioral responses. Female prairie voles (Microtus ochrogaster) underwent a stressor (walking in shallow water) following pretreatment with intraperitoneal OXT (0.25 mg/kg) or OXT antagonist (OXT-A, 20 mg/kg), and were allowed to recover with or without their sibling cagemate. Administration of OXT resulted in elevated OXT concentrations in plasma, but did not dampen the HPA axis response to a stressor. However, OXT, but not OXT-A, pretreatment prevented the functional coupling, usually seen in the absence of OXT, between paraventricular nucleus (PVN) activity as measured by c-Fos immunoreactivity and HPA output (i.e. corticosterone release). Furthermore, OXT pretreatment resulted in functional coupling between PVN activity and brain regions regulating both sympathetic (i.e. rostral ventrolateral medulla) and parasympathetic (i.e. dorsal vagal complex and nucleus ambiguous) branches of the autonomic nervous system. These findings suggest that OXT increases central neural control of autonomic activity, rather than strictly dampening HPA axis activity, and provides a potential mechanism through which OXT may facilitate adaptive and context-dependent behavioral and physiological responses to stressors

Acoustic features of prairie vole (Microtus ochrogaster) ultrasonic vocalizations covary with heart rate

Vocalizations serve as a conspecific social communication system among mammals. Modulation of acoustic features embedded within vocalizations is used by several mammalian species to signal whether it is safe or dangerous to approach conspecific and heterospecific mammals. As described by the Polyvagal Theory, the phylogenetic shift in the evolution of mammals involved an adaptive neuroanatomical link between the neural circuits regulating heart rate and the muscles involved in modulating the acoustic features of vocalizations. However, few studies have investigated the covariation between heart rate and the acoustic features of vocalizations. In the current study, we document that specific features of vocalizations covary with heart rate in a highly social and vocal mammal, the prairie vole (Microtus ochrogaster). Findings with the prairie vole illustrate that higher pitch (i.e., fundamental frequency) and less variability in acoustic features of vocalizations (i.e., less vocal prosody) are associated with elevated heart rate. The study provides the first documentation that the acoustic features of prairie vole vocalizations may function as a surrogate index of heart rate

Autonomic Substrates of the Response to Pups in Male Prairie Voles

Caregiving by nonparents (alloparenting) and fathers is a defining aspect of human social behavior, yet this phenomenon is rare among mammals. Male prairie voles (Microtus ochrogaster) spontaneously exhibit high levels of alloparental care, even in the absence of reproductive experience. In previous studies, exposure to a pup was selectively associated with increased activity in oxytocin and vasopressin neurons along with decreased plasma corticosterone. In the present study, physiological, pharmacological and neuroanatomical methods were used to explore the autonomic and behavioral consequences of exposing male prairie voles to a pup. Reproductively naïve, adult male prairie voles were implanted with radiotransmitters used for recording ECG, temperature and activity. Males responded with a sustained increase in heart-rate during pup exposure. This prolonged increase in heart rate was not explained by novelty, locomotion or thermoregulation. Although heart rate was elevated during pup exposure, respiratory sinus arrhythmia (RSA) did not differ between these males and males exposed to control stimuli indicating that vagal inhibition of the heart was maintained. Blockade of beta-adrenergic receptors with atenolol abolished the pup-induced heart rate increase, implicating sympathetic activity in the pup-induced increase in heart rate. Blockade of vagal input to the heart delayed the males’ approach to the pup. Increased activity in brainstem autonomic regulatory nuclei was also observed in males exposed to pups. Together, these findings suggest that exposure to a pup activates both vagal and sympathetic systems. This unique physiological state (i.e. increased sympathetic excitation of the heart, while maintaining some vagal cardiac tone) associated with male caregiving behavior may allow males to both nurture and protect infants

The Science Case for an Extended Spitzer Mission

Although the final observations of the Spitzer Warm Mission are currently scheduled for March 2019, it can continue operations through the end of the decade with no loss of photometric precision. As we will show, there is a strong science case for extending the current Warm Mission to December 2020. Spitzer has already made major impacts in the fields of exoplanets (including microlensing events), characterizing near Earth objects, enhancing our knowledge of nearby stars and brown dwarfs, understanding the properties and structure of our Milky Way galaxy, and deep wide-field extragalactic surveys to study galaxy birth and evolution. By extending Spitzer through 2020, it can continue to make ground-breaking discoveries in those fields, and provide crucial support to the NASA flagship missions JWST and WFIRST, as well as the upcoming TESS mission, and it will complement ground-based observations by LSST and the new large telescopes of the next decade. This scientific program addresses NASA's Science Mission Directive's objectives in astrophysics, which include discovering how the universe works, exploring how it began and evolved, and searching for life on planets around other stars.Comment: 75 pages. See page 3 for Table of Contents and page 4 for Executive Summar