**2. Handoff in heterogeneous wireless networks**

Since the integration of widely deployed 3G cdma2000 and WLAN can give a lot of benefits to both end users and service providers, there has been a lot of researches about interworking mechanism between cdma2000 and WLAN (3GPP, 2003; Ahmavaara et al., 2003; Buddhikot et al., 2003; Luo et al., 2003; Salkintzis, 2004). The WLAN and 3G cdma2000 integration architecture is characterized by the amount of interdependence it introduces between the two component networks. Two candidate integration architectures, tightly-coupled and loosely-coupled interworking are described in Fig. 1.

Fig. 1. Interworking architecture of heterogeneous wireless networks

In the tightly-coupled interworking approach, WLAN networks appear to 3G core network as another 3G RAN (Radio Access Network). The WLAN gateway hides the details of the WLAN network to the 3G core network, and implements all the 3G protocols. Even though this approach can share the same authentication, signaling, and billing infrastructures, independent from physical layer interface, it has a disadvantage that the capacity and configuration of each network element is carefully reengineered and can result in high cost. On the contrary, the loosely-coupled interworking approach has several advantages such that 3G networks and WLAN can be independently deployed without extensive capital investments and its implementation is relatively easy. Therefore, it has emerged as a preferred

Fig. 2. L3 handoff procedure

2 Mobile Networks

The paper is organized as follows: Section 2 summarizes existing techniques for handoff scheme as related work. Section 3 presents the proposed L2 handoff scheme and we describe the performance characteristics of the proposed scheme through OPNET simulation in Section

Since the integration of widely deployed 3G cdma2000 and WLAN can give a lot of benefits to both end users and service providers, there has been a lot of researches about interworking mechanism between cdma2000 and WLAN (3GPP, 2003; Ahmavaara et al., 2003; Buddhikot et al., 2003; Luo et al., 2003; Salkintzis, 2004). The WLAN and 3G cdma2000 integration architecture is characterized by the amount of interdependence it introduces between the two component networks. Two candidate integration architectures, tightly-coupled and

4. Section 5 concludes the paper.

**2. Handoff in heterogeneous wireless networks**

loosely-coupled interworking are described in Fig. 1.

Fig. 1. Interworking architecture of heterogeneous wireless networks

In the tightly-coupled interworking approach, WLAN networks appear to 3G core network as another 3G RAN (Radio Access Network). The WLAN gateway hides the details of the WLAN network to the 3G core network, and implements all the 3G protocols. Even though this approach can share the same authentication, signaling, and billing infrastructures, independent from physical layer interface, it has a disadvantage that the capacity and configuration of each network element is carefully reengineered and can result in high cost. On the contrary, the loosely-coupled interworking approach has several advantages such that 3G networks and WLAN can be independently deployed without extensive capital investments and its implementation is relatively easy. Therefore, it has emerged as a preferred architecture for the integration of WLAN and 3G networks. As previously mentioned, the L3 handoff procedure is commonly used to provide mobility services in the loosely coupled interworking architecture. Mobile IP is the representative technology of L3 handoff to provide mobility services within homogeneous 3G cdma2000 or between 3G cdma2000 and WLAN. When mobile station moves into new wireless network, Mobile IP performs registration procedure and handoff are completed after registration procedure as shown in Fig. 2(a). The low-latency handoff for Mobile IP (Maki, 2004) is proposed to reduce packet loss occurred in the registration procedure. It reduces packet loss by providing tunneling and buffering between the previous and new networks as depicted in Fig. 2(b). Since the current cdma2000 networks employ Mobile IPv4, we deal with Mobile IPv4 and its extended version in this paper. So the low latency handoff for Mobile IPv4 in Fig. 2(b) will be used in performance evaluation of Section 4. In IPv6 environment, however, fast handoff for Mobile IPv6 (Koodli, 2005) can be considered similarly.


As a federal agency, NASA is required to furnish its employees with a workplace that is free from recognized hazards such as ionizing radiation that are causing, or likely to cause, death or serious physical harm (65). NASA is also required to establish and operate an occupational safety and health program to protect workers. Recognizing the unique needs of space exploration, the federal Occupational Safety and Health Administration (OSHA) granted NASA a waiver from ground based radiation standards while requiring it to establish supplemental standards appropriate for space missions (1, 66). NASA's Office of the Chief Medical and Health Officer is responsible for setting these standards, and issued a series of documents including NASA Procedural Requirements (NPR) 8900.1A (NASA Health and Medical Requirements for Human Space Exploration) and NPD 8900.5B (Health and Medical Policy for Human Space Exploration) in response (67, 68). In addition, NASA STD-3001, chapter 6, explicitly addresses ionizing protection in space environments (69).

# Overview of GINA

The GINA, codified as 42 US §§2000ff, is a federal law that prohibits employment discrimination on the basis of genetic information (70). This statute has two major sections. Title I covers group health plans and insurers. Title II covers employers, such as NASA, and prohibits them from discriminating against employees and job applicants based on genetic information. It also prohibits employers from collecting genetic information, except under very limited circumstances. The US Equal Opportunity Employment Commission (EEOC), an independent commission charged with enforcing federal laws against job discrimination,

oversees GINA and has issued regulations to implement it (see 29 CFR §§1635.1 to 1635.12) (71). This article focuses on Title II of GINA and examines how its provisions could impact the implementation of the four approaches to personalized cancer risk assessments, summarized in **Table 1** and set out earlier in this article.

This statute and its implementing regulations are relatively new, and interpretation of its provisions is evolving [e.g., Ref. (72)]. The discussion of the applicability of GINA to NASA is based on the information available at the time of publication, and it is possible that subsequent events, especially litigation brought under GINA, could impact the way in which GINA is interpreted. The analyses are based on generalized circumstances and are not intended to provide legal advice.

One of the central provisions of GINA is that "it is an unlawful employment practice for an employer to request, require, or purchase genetic information with respect to an employee" [42 USC §2000ff-1(b)]. This provision turns on how the statute defines the term "genetic information." Under GINA, this term means information about an individual that includes "(i) such individual's genetic tests, (ii) the genetic tests of family members of such individual, and (iii) the manifestation of a disease or disorder in family members of such individual" [42 USC §2000ff(4)]. In addition, the term "genetic test" is "an analysis of human DNA, RNA, chromosomes, proteins, or metabolites, that detects genotypes, mutations, or chromosomal changes" [42 USC 2000ff(7)].

# Collecting and Using Personalized Information for Space Radiation Risk Assessments

This article discusses four approaches to supplement personalized cancer risk assessments. The first approach would incorporate family and personal medical history, especially for breast cancer and CRC, into these assessments. The second approach would collect information about microtumors or preneoplastic cells that could undergo promotion and/or progression by radiation exposures to malignancies. The third and fourth approaches would rely on evaluations of radiosensitivity based on genotypic and phenotypic assays. Each of these approaches would seem to trigger the collection of genetic information under GINA and therefore would most likely be prohibited under the statute. The first approach falls squarely within GINA's prohibition of collecting personal and family medical information. The second approach would rely on the evaluation of cells and tissues based on their mutations, which also is a prohibited activity under GINA. The third and fourth approaches are keyed to radiosensitivity or genotype to phenotype associations, which again would require the collection of data that falls squarely within GINA's purview. In summary, based on GINA's intent and its statutory language, it appears that the data and methodologies set forth in this article that would be needed for personalization of cancer risk assessment would be prohibited by GINA. More specifically, under GINA it seems clear that NASA could not collect nor use to make employment decisions, information based on personalized cancer risk assessments that use the approaches set out in **Table 1**.

Two potential uses of more personalized cancer risk assessments are to screen NASA applicants and reduce employment risks to astronauts who are sent on space missions. GINA prohibits the use of genetic information and genetic tests for pre-employment screening. As this article points out, at present NASA's approach to setting permissible exposure limits relies on a cancer risk assessment model that takes into account the astronaut's age at exposure, sex, and smoking status. From a scientific perspective, this article suggests that among the steps to model improvement would be to utilize the increasingly powerful and more precise technologies that employ what, under GINA, would be classified as "genetic information" and "genetic tests." Construing the statute as currently interpreted, it would seem that collecting and using this information would contravene this law and its regulations.

# PostFlight Monitoring and GINA

This article also suggests that postflight monitoring is potentially beneficial for astronauts. Such monitoring could result in reduced mortality for some tumor types, because early detection of tumors or pre-cancerous conditions could mean more effective, and timely, intervention. In this regard, GINA contains an exception to the collection of genetic information for employers who want to collect such information to assess the biological effects of toxic substances in the workplace. The employer can offer health and/or genetic services to employees in the form of a confidential wellness and/or counseling program. GINA requires that such information can be collected and used if the employee provides voluntary written authorization before collection; only the employee and family members and the genetic counselor receive this information; and that the individual genetic information not be disclosed to employers [42 USC §2000ff-1(b)(5)]. Under this section of GINA, it might be possible to collect and use the type of genetic information that is contemplated by the approaches outlined in this article. Such information might be disclosable to NASA "only in aggregate terms that do not disclose the identity of specific employees" [42 USC §2000ff – 1(b)(5)(E)].

# REFERENCES

# AUTHOR CONTRIBUTIONS

MW provided the discussion of various approaches available to personalize risk assessment for radiation carcinogenesis. PL evaluated the impact of the Genetic Information Nondiscrimination Act on the use of these approaches.

# FUNDING

Research by MW is supported by grants NNX12AB54G and NNX15AK13G from the National Aeronautics and Space Administration.

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer, Eliedonna Cacao and handling Editor, Francis A. Cucinotta declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.

*Copyright © 2016 Locke and Weil. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Radiation Measurements Performed with Active Detectors Relevant for Human Space Exploration

*Livio Narici1,2\*, Thomas Berger2 , Daniel Matthiä2 and Günther Reitz2*

*1Department of Physics University of Rome Tor Vergata and INFN-Roma2, Rome, Italy, 2 Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany*

A reliable radiation risk assessment in space is a mandatory step for the development of countermeasures and long-duration mission planning in human spaceflight. Research in radiobiology provides information about possible risks linked to radiation. In addition, for a meaningful risk evaluation, the radiation exposure has to be assessed to a sufficient level of accuracy. Consequently, both the radiation models predicting the risks and the measurements used to validate such models must have an equivalent precision. Corresponding measurements can be performed both with passive and active devices. The former is easier to handle, cheaper, lighter, and smaller but they measure neither the time dependence of the radiation environment nor some of the details useful for a comprehensive radiation risk assessment. Active detectors provide most of these details and have been extensively used in the International Space Station. To easily access such an amount of data, a single point access is becoming essential. This review presents an ongoing work on the development of a tool that allows obtaining information about all relevant measurements performed with active detectors providing reliable inputs for radiation model validation.

Keywords: active radiation detectors, International Space Station, human space exploration, space radiation risk, database

# INTRODUCTION

Space radiation risks (on humans and instrumentation) are possibly the most severe challenge posed to human exploration of deep space (1). A reliable space radiation risk assessment requires further understanding in radiation biology and also more details about the characteristics of the radiation.

Future mission planning will be based on radiation models which will have to be able to describe to a sufficient level of accuracy the radiation environment the crew will be living in. Such models are under development and consist of a combination of source models, transport models, and computeraided design (CAD) ability to describe the habitat (either a spacecraft or a space base). Each part as well as the entire final model will have to be properly validated by measurements, and consequently, these measurements will have to provide a similar degree of detail as the model. Passive detectors cannot provide information about, for example, temporal and spatial evolution, or the primary kinetic energy of the ions. Often not even active detectors permit to measure all these parameters.

The construction of future space vessels and space bases is expected to be of similar complexity compared to the International Space Station (ISS). This makes the ISS an important "validation habitat" for the mentioned radiation models. The radiation impinging on the ISS is, however,

#### *Edited by:*

*Marco Durante, GSI, Germany*

#### *Reviewed by:*

*Evagelia C. Laiakis, Georgetown University, USA Ulrich H. Straube, European Space Agency, Germany*

> *\*Correspondence: Livio Narici<EMAIL_ADDRESS>
#### *Specialty section:*

*This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology*

*Received: 30 September 2015 Accepted: 23 November 2015 Published: 08 December 2015*

#### *Citation:*

*Narici L, Berger T, Matthiä D and Reitz G (2015) Radiation Measurements Performed with Active Detectors Relevant for Human Space Exploration. Front. Oncol. 5:273. doi: 10.3389/fonc.2015.00273*

modulated by the Earth magnetic field, and thus it has features that are not found in deep space. In particular, primary cosmic radiation at low latitude is heavily reduced comprising only high energy ions; charged particles with lower energies are deflected by the magnetic field. At high latitudes, this shielding effect of the magnetic field is much weaker and the radiation field is more similar to the one encountered in deep space.

Furthermore, in a region above Brazil (South Atlantic Anomaly, SAA), the tilt and shift of the magnetic dipole-axis compared to the rotation-axis of Earth result in a close approach of the radiation belt to the Earth's surface. In the radiation belt, a large amount of low charge ions (mostly protons) of relatively low energy is trapped.

Due to the latitude-dependent magnetic shielding and the presence of the SAA active detectors are advantageous for model validation for deep space; they can be used to select measurements from specific geographical regions and permit to construct a proper dataset for validation, i.e., from high latitudes.

Ideally, measurements and model developments should proceed in a process defining both the most suitable areas in the ISS to perform experiments and the required parameters that are to be measured. Although this approach is usually not realized, a high number of measurements have been and are being performed, which are useful for model validation.

Teams working on radiation models and looking for data for validation often encounter difficulties as literature searches are not always fruitful. Sometime this is due to the difficulty to extract numerical values from articles or it can be due to the delay in the publication procedure. Also, these searches are most often quite time consuming. Therefore, researchers heavily rely on personal communications from teams they have ongoing collaborations with.

It is obvious that a far better approach is having a single access point where all data can be found. In the future, this should lead to a worldwide accessible database. In order to foster the development of such a database and to provide to the scientific community a simple tool for the fast and successful identification of suitable data, a *search book* is being created in which all relevant information is to be collected.

This review provides a description of this *search book* that is a soon to be web-published compilation of basic information on active detector measurements of radiation environment for human exploration risk assessment, in particular, when, where (in the ISS or also in or on other relevant satellites/spacecraft), how (what kind of active detector, what kind of measurement), and who (a contributor for each dataset to whom any question about the corresponding data might be addressed).

The goal is to provide this information interactively available on the web. As this work is ongoing the list of active detectors in this article is not complete, and it will be a continuing task to update the data.

# TIME FRAME AND MEASUREMENTS CONSIDERED

This review covers the ISS life span and includes also measurements performed during the same period at locations different than ISS, provided that they are of relevance for human space exploration. There are several reasons why the ISS is an ideal starting point:

Concurrent measurements on Earth satellites as well as around Moon or Mars and in interplanetary space are also extremely important as they provide information about the radiation sources impinging on the ISS.

# THE SUMMARY TABLES

**Table 1** shows the measurement locations in the past 16 years, as well as the detector performing each measurement. A filled box indicates that measurements were taken during that year. Further details about the time and duration of each measurement as well as detector characteristics and relevant operational parameters will be provided on the web site.

We give a brief account of the latter in **Table 2** together with an email address as contact point for each of the considered instruments. For any further information and details, the reader is addressed to the references.

# A BRIEF DESCRIPTION OF THE DETECTORS

The *R-16* detector (2–9) is a combination of two Argon filled ionization chamber with two different shielding. It has been also the first active detector in use in the ISS.

*The DB-8* (2–9) detector is similar to the Liulin (see below). Four DB-8 units are a part of the ISS radiation monitoring system (RMS). All the DB-8 units are identical and two independent sensors with different shielding operate in each of the DB-8 units. The DB-8 units were located in different locations in the ZVEDA module to provide measurements in different shielding environments.

*Liulin* (10–42) labels a set of small detectors of very similar dimensions and operational principles but differing in read out, storing, and other characteristics that tailored each detector to the experiments it was built for. Details on these instruments can be found in the references, e.g., Ref. (40). All Liulin-type instruments use silicon detectors and measure the deposited energy and the number of charged particles hitting the device, which can be converted to dose rate and particle flux. The first Liulin was developed in the late 80s (43) for use in the MIR Station. The ISS instruments are Liulin-E094 (April to August 2001),

#### TABLE 1 | Overview of active detector measurements since the beginning of the ISS era.

*Filled boxes indicate years in which measurements have been performed with the corresponding detector and on the corresponding location. To obtain more detailed information about the exact timing, the reader is suggested to read the relative references or contact the contact point (see Table 2). The table is still not complete (work in progress, see text).*

TABLE 2 | Details of the active radiation detectors that have been active on the ISS or that have performed measurements relevant to human exploration.

*a Hemisphere connected with a cylinder, the internal radius of the hemisphere and the cylinder being 20 mm, the height of the cylinder being 20 mm. bSeveral instruments in this family: Liulin-E094, Liulin-ISS, Liulin-Photo, RADOM, R3DE, R3DR, R3D-B2, R3D-B3.*

*c See also Liulin-5 references.*

*dFour CPDS: one intra-vehicular (IV-CPDS) and three extra-vehicular (EV-CPDS).*

*e Six identical telescopes deployed in different configurations: on an helmet-like holder, in a X, Y, and Z configuration, in a flat configurations.*

*f See also Liulin references.*

*g Several instruments in this family: DosMap-Dostel, MTR-Dostel, EuTEF-Dostel, Dosis-Dostel.*

*h Two sensors for each of the three cartesian directions (X, Y, Z) for a total of 6.*

*i PAMELA silicon tracker is part of a complex instrument featuring also a permanent magnet as well as a time of flight system (based on 6 fast plastic scintillators and a calorimeter. See references).*

*j Each pair of sensors (thin–thick) is sandwiched on tissue equivalent plastic.*

*k Depending on the coincidence choice.*

*l RAD includes also a CsI(Tl) scintillator, a plastic scintillator, and an anti-coincidence system, see references.*

*mThe top sensor is segmented into two rings, others are like the inner part of A, see references.*

*Further details in the references.*

Liulin-ISS (September 2005 to June 2014), Liulin-5 (May 2007 to present), R3DE (February 2008 to September 2009), and R3DR (March 2009 to August 2010), the latter two have been deployed outside the ISS. Several Liulins (R3D-B2, R3D-B3, Liulin-Photo) have also been used in Foton and Bion satellites flying in Low Earth Orbit (LEO) and in the Chandrayaan-1 satellite around the moon (RADOM). The Liulin-5 (75–82) is the first of a new Liulin type: it is a telescope using three silicon detectors providing both a coincidence (telescope) and a non-coincidence read out (for direct dose measurements).

The charged particle directional spectrometer (*CPDS*) (44, 45) is a detector used by NASA to monitor ISS radiation environment. It is a telescope with a 12 element silicon stack with different thickness (6 thick, 5 mm and 6 thinner, 0.3 and 1 mm) and a Cerenkov detector at the bottom. Thick detectors are for particle identification. The individual sensor cards are identical in design to those used on the MARIE instrument (see below). Three CPDS have been deployed externally (EV-CPDS). EV1-CPDS and EV3- CPDS were aligned with the +*X* and −*X* axis in the ISS coordinate system, while EV2-CPSDS with the −*Z* axis. Another detector (IV-CPDS) was deployed inside the USLab initially pointing to the +*X* direction and since 8 August 2006 to the +*Z* direction.

*Alteino* (46–52), often referred to as SilEye3, is an upgraded SilEye (53), which was successfully deployed in the MIR station. As all the ALTEA systems it originates from investigations of the radiation potentially causing the "Light Flash" anomalous perception to the astronauts [Ref. (54) and references therein]. Alteino features a stack of eight silicon striped sensors (each 80 mm × 80 mm × 0.38 mm) and two plastic scintillators: one in front of and one behind the silicon stack. Sensors are segmented in alternating directions (*X* and *Y*). The direction and the height in the stack of eight provide a set of three coordinates for each sensor traversal and for each particle, and permit to track its direction. Alteino is a pure telescope recording radiation only when both scintillators are hit. The detector has the size of a shoebox, and it is able to measure the LET in silicon and the flux and the trajectory of each ion, using the ability to know which of the sensor strip has been hit. Alteino was deployed in the Russian segment of the ISS, in the Russian space program and then in an ESA sponsored experiments under the ALTCRISS project. Alteino data were downloaded periodically via PCMCIA cards. Alteino provided detailed particle spectra in the Russian modules.

*ALTEA* (55–74) is a system of six identical silicon telescopes. Each telescope is similar to Alteino (also in size) but lacking the scintillators and featuring six striped silicon sensors with twice the area of the sensors used in Alteino (each 160 mm × 80 mm × 0.38 mm). The bi-directional geometrical factor is 230 cm2 sr and the system is auto-triggered by traversing ions. The six telescopes are identical and in the periods of interest have been deployed either on a helmet shaped holder in different locations in the USLab, on a three axis (*X*, *Y*, and *Z*) holder in other locations in the USLab or in a flat configuration for measuring effectiveness of shielding materials in one location in Columbus. ALTEA data are downlinked via real time telemetry. A software package on ground provides flux, dose, dose equivalent, and spectra in real time. ALTEA ISS surveys allowed for the 3D characterization of the radiation environment in the USLab (relevant for model validation). Also of relevance is the study of the iron abundance (ISS – USLab), which is apparently lower than expected.

*DosTel* (16, 83–89) is a detector family based on two silicon detectors, each with an area of 6.94 cm2 arranged in telescope geometry. With this setup, the DosTel applied for various experiments onboard space stations and shuttle missions can measure energy deposition of radiation hitting a detector ("dose mode") or coincidental hits in the two detectors ("telescope" or "LET" mode). From 2009 onward, two identical DosTel units have been deployed in Columbus looking in two directions (*X* and *Y*). The long duration of the DosTel measurements in Columbus permits to study the variation of the radiation during a long solar modulation period.

*TRITEL* (90–95) is a set of three small two elements silicon telescopes, mounted in a 3D configuration (*X*, *Y*, and *Z*). Each telescope is made of two sensors, 220 mm × 0.3 mm, and has a geometrical factor of 5.1 cm2 sr. All sensors are identical, fully depleted, passivated implanted planar silicon (PIPS) detectors. TRITEL has been deployed in the ISS since 2012. TRITEL has been deployed in the Columbus modulus in the EPM rack (TRITEL-SURE, close to DosTel) and in the Zvezda modulus (TRITEL-RS).

*PAMELA* (96–112) was developed from an instrument that flew aboard the balloon missions MASS, TS93, and CAPRICE, with a design optimized for the study of antimatter in the cosmic radiation. For this type of investigation, it is necessary to have information about the particle charge, energy, and type of interaction from several redundant sub-detectors, in order to uniquely identify rare particles from background. It is composed of a Time-of-Flight (ToF) system, a magnetic spectrometer (MS), a sampling electromagnetic calorimeter (SeC), and a neutron detector (ND).

The ToF comprises six layers of fast plastic scintillators arranged in three double planes (S1, S2, and S3), with alternate layers placed orthogonal to each other. ToF information for charged particles is combined with track length information from the MS to determine particle velocities; particle charge (*Z*) can be determined up to *Z* = 8.

The MS consists of a permanent magnet and a silicon tracker (six equidistant 300 μm thick silicon detector planes inserted inside the magnetic cavity). Ionization loss measurements are also made in the silicon planes.

The SeC is made of 44 single-sided silicon sensor layers (380 μm thick) interleaved with 22 plates of tungsten absorber. The main task of the calorimeter is to select positrons and antiprotons from like-charged backgrounds, and it is therefore not of interest in our case; however, it also provides a measurement of the energy of the incident electrons independent from the MS, thus allowing a cross-calibration of the two energy determinations.

The ND is placed below the calorimeter with the aim to increase the electromagnetic and hadronic discrimination capability of the Pamela instrument.

PAMELA's most important scientific results are related to the anomalous positron abundance. Here, however, the highest interest is in the extraordinary spectrometric ability in the low energy regime (below few GeV/n) for small *Z* (*Z* < 8) ions.

*MARIE* (113–118) is a telescope with an eight element silicon stack with Cerenkov detector at the bottom with different thickness (4 thick, 5 mm and 4 thinner, 0.3 and 1 mm). Thick detectors are for particle identification. The individual sensor cards are identical in design to those used on the CPDS instrument (see above). MARIE has been mounted on Odyssey's equipment deck, pointing opposite to the spacecraft's velocity vector. Odyssey is in a circular 2-h polar orbit around Mars. Forward field of view (FOV) points into deep space, rear FOV is partially blocked by Mars. MARIE performed the first characterization of the Martian radiation environment aimed at the risk assessment for human exploration.

*CRaTER* (119–126) is a telescope with three silicon detector pairs sandwiching pieces of tissue-equivalent plastic. Each pair has one thin detector (150 mm) for measuring high-LET particles and one thick detector (1 mm) for low-LET particles. CRaTER is part of LRO in orbit around the Moon. In nominal orbit, one end of telescope points zenith, the other nadir (toward lunar surface) with the rear FOV entirely filled by the lunar disk. LRO was in a circular 2-h polar orbit above the Moon for the prime mission and is now in an elliptical orbit. The overall dimensions are 24 cm × 23 cm × 16 cm. Of important is the long period of observations that permits to investigate the evolution of the deep space radiation environment during the solar cycle.

*RAD* (127–135) is a three-element silicon stack, a CsI(Tl) scintillator with p-i-n diode readout and a plastic scintillator at the bottom of the stack; an anti-coincidence system surrounds the CsI(Tl) scintillator and the plastic scintillator and enables their use as neutral particle detectors. It is mounted on the top deck of Curiosity rover pointing to the zenith. The rover is controlled so that tilt does not exceed 10°. During cruise phase, RAD was shielded from above by the Descent Vehicle and from below by the heat shield. On Mars, RAD was shielded by Martian atmosphere (~20 g cm<sup>−</sup><sup>2</sup> CO2). The detector is small (mass 1.56 kg, total volume 240 cm3 ) and has several coincidence and anti-coincidence capabilities. RAD allowed for the first detailed measurements of the Mars surface radiation environment.

# ACTIVE DETECTORS IN SPACE: THE FUTURE

With the advances of the field, active detectors may partly replace passive detectors. Power requirements as well as required sensor dimensions are slowly entering the region of acceptability for a widespread use in space, both as area detectors (for which constraints on dimensions and power are not so strong and therefore requirements for detailed measurement of the radiation field can be fulfilled) and as personal detectors. In the latter case, the miniaturization would not allow for a complete characterization of the radiation field. Nevertheless, active personal dosimeters certainly would provide a more comprehensive picture than passive detectors, and they would permit real time monitoring

# REFERENCES

and alarming capabilities [see, for example, Ref. (136)]. It would be desirable that the data of all future active devices flow into a network of databases in order to make it available in quasi real time for all interested teams.

# CONCLUSION

The development of a *search book* comprising information about radiation measurements relevant for the validation of models for human exploration has been reported. While not yet complete the extent of measurements of active detectors is already impressive and constitutes a valuable tool for anyone developing or validating radiation models for deep space spacecraft or habitats.

Complementing information about other measurements and detectors will be added in the future, and a similar approach for passive detectors should be started. A final output on a web page is foreseen.

# AUTHOR CONTRIBUTIONS

All authors (LN, TB, DM, and GR) have participated to the idea and to the writing of the Search Book and of this first mini review.

# ACKNOWLEDGMENTS

The authors acknowledge the very important help given by all the researchers that collaborated in providing information about the devices they are or have been working with. Specifically, V. V. Benghin, M. Casolino, T. P. Dachev, A. Hirn, K. T. Lee, V. A. Shurshakov, J. V. Semkova, R. Sparvoli, and C. Zeitlin.

International Space Station during the period 2005-2011. *Cosmic Research* (2012) **50**:391–6. doi:10.1134/S0010952512050036

of radiation doses distribution in a human phantom aboard the International Space Station. *C R Acad Bulg Sci* (2008) **61**:787–94.

effects on high-energy solar particles. *Astrophys J Lett* (2015) **801**:L3. doi:10.1088/2041-8205/801/1/L3

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2015 Narici, Berger, Matthiä and Reitz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# The Role of Nuclear Fragmentation in Particle Therapy and Space Radiation Protection

#### *Cary Zeitlin1 \* and Chiara La Tessa2*

*<sup>1</sup> Lockheed Martin Information Services & Global Solutions, Houston, TX, USA, 2Collider-Accelerator Department, Brookhaven National Laboratory, Upton, NY, USA*

The transport of the so-called HZE particles (those having high charge, *Z*, and energy, E) through matter is crucially important both in space radiation protection and in the clinical setting where heavy ions are used for cancer treatment. HZE particles are usually considered those having *Z* > 1, though sometimes *Z* > 2 is meant. Transport physics is governed by two types of interactions, electromagnetic (ionization energy loss) and nuclear. Models of transport, such as those used in treatment planning and space mission planning must account for both effects in detail. The theory of electromagnetic interactions is well developed, but nucleus–nucleus collisions are so complex that no fundamental physical theory currently describes them. Instead, interaction models are generally anchored to experimental data, which in some areas are far from complete. The lack of fundamental physics knowledge introduces uncertainties in the calculations of exposures and their associated risks. These uncertainties are greatly compounded by the much larger uncertainties in biological response to HZE particles. In this article, we discuss the role of nucleus–nucleus interactions in heavy charged particle therapy and in deep space, where astronauts will receive a chronic low dose from galactic cosmic rays (GCRs) and potentially higher short-term doses from sporadic, unpredictable solar energetic particles (SEPs). GCRs include HZE particles; SEPs typically do not and we, therefore, exclude them from consideration in this article. Nucleus–nucleus collisions can result in the breakup of heavy ions into lighter ions. In space, this is generally beneficial because dose and dose equivalent are, on the whole, reduced in the process. The GCRs can be considered a radiation field with a significant high-LET component; when they pass through matter, the high-LET component is attenuated, at the cost of a slight increase in the low-LET component. Not only are the standard measures of risk reduced by fragmentation, but it can be argued that fragmentation also reduces the uncertainties in risk calculations by shifting the LET distribution toward one that is more concentrated at low LET, where biological effects are better understood. We review previous work in this area, including measurements made by the Radiation Assessment Detector during its journey to Mars and while on the surface of Mars aboard the Curiosity rover. Transport of HZE is also critically important in heavy-ion therapy, as it is necessary to know the details of the radiation field at the treatment site. This field is substantially modified compared to the incident pure (or nearly pure) ion beam by the same mechanisms of energy loss and nuclear fragmentation that pertain to the transport of space radiation.

Keywords: galactic cosmic rays, nuclear fragmentation models, nuclear interactions, Bragg curve, space radiation, space radiation shielding, heavy-ion therapy

#### *Edited by:*

*Marco Durante, GSI Helmholtz Centre for Heavy Ion Research, Germany*

#### *Reviewed by:*

*Vincenzo Patera, Sapienza University of Rome, Italy Lawrence Harvey Heilbronn, University of Tennessee, USA*

> *\*Correspondence: Cary Zeitlin<EMAIL_ADDRESS>
#### *Specialty section:*

*This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology*

*Received: 01 December 2015 Accepted: 07 March 2016 Published: 29 March 2016*

#### *Citation:*

*Zeitlin C and La Tessa C (2016) The Role of Nuclear Fragmentation in Particle Therapy and Space Radiation Protection. Front. Oncol. 6:65. doi: 10.3389/fonc.2016.00065*

# INTRODUCTION

The situation for cancer treatment with beams of heavy charged particles is quite different from that in space, but there is important overlap between the transport physics in the two settings. In the clinic, dose localization is of paramount importance, but nuclear fragmentation degrades localization. By contrast, the same process is beneficial in space, because high-LET particles are broken up into particles with lower LET and (in most cases) reduced biological effectiveness.

Fragmentation significantly complicates treatment planning, because the lower-LET particles produced in these reactions have greater ranges than the primary beam ions and, therefore, deposit energy beyond the distal edge of the Bragg peak. Low-LET particles may also be produced at significant angles with respect to the incoming beam, resulting in a lateral leakage of dose into healthy tissues. Target fragments, which consist of short-ranged, high-LET charged particles and neutrons, are emitted more or less isotropically from the struck nucleus, and may cause very large energy deposits anywhere along the path of the incident ion. Such reactions are particularly undesirable when they occur in the entrance region, since they tend to undermine one of the primary benefits of heavy ions for therapy, the large peak-toplateau dose ratio. Target fragments are also produced by proton beams and complicate treatment planning in that modality (1).

These effects, particularly the irradiation of healthy tissues beyond the distal edge of the Bragg peak, effectively limit the maximum ion charge that can be used in treatment. For any given beam ion species, and any given depth of treatment volume, it is possible to find a beam energy that will yield a Bragg peak in the desired location. This might seem to suggest that the highest possible *Z* should be used, in order to maximize the peak-to-plateau ratio of biological dose. However, the distal edge problem worsens significantly with increasing beam charge. In the early days of heavy-ion therapy at the Lawrence Berkeley Laboratory's Bevalac, ions as heavy as neon (*Z* = 10) were used. Current practice in Japan and Europe has largely been focused on carbon ions (*Z* = 6) as representing a more optimal trade. Helium ions (*Z* = 2, mass number 4) are also of considerable interest, and our analysis of recently obtained cross-sectional data suggests that they may provide a localization advantage. This arises from the fact that the nucleons in helium nuclei are especially tightly bound, making them relatively less likely to fragment. When they do undergo fragmentation, the most copiously produced isotope is 1 H, which for a given kinetic energy per nucleon has almost exactly the same range as 4 He. This fact significantly reduces the distal edge problem, though deuterons (2 H) and neutrons produced in fragmentation reactions do deposit some energy in the distal edge.

In space, exposure to heavy ions increases cancer risk; in medicine, the same ions may be used to treat cancer. In the following, we will compare and contrast the effects of nuclear fragmentation in these two environments. An extensive literature on nuclear reactions relevant to spaceflight exists, and was recently reviewed by Norbury et al. (2) Since the beginning of human spaceflight, it has been recognized that energetic charged particles pose a health risk to explorers. When mission durations were short, on the order of hours or days and confined to low-Earth orbit (LEO), the main concerns were exposure to large solar-particle events (SPEs) and trapped radiation. SPEs, which typically produce protons with kinetic energies below 100 MeV, are a concern even on short missions for two reasons: first, because they can produce high dose rates, particularly in situations where shielding is minimal, and, second, because they are unpredictable and sometimes have sudden onsets (3). In LEO, there is geomagnetic shielding of galactic cosmic rays (GCRs) and also partial blocking of particle fluxes by the Earth (roughly a 35–40% effect, depending on altitude). Exposure to GCRs in LEO gives a small but steady dose rate, on the order of 100–300 μGy/ day depending on the phase of the solar cycle; in such orbits, there is a roughly equal contribution from trapped radiation, so that in the absence of SPEs, total doses are well under 1 mGy/ day. Considering that, in the ICRP 60 formulation (4), the average radiation quality factor in space is in the range from 6 to 7 (less behind shielding), this leads to exposures of <5 mSv/day in terms of dose equivalent. Although this is a far higher rate than encountered on Earth (about 4 mSv/year average in the United States), such exposures are not of concern for mission durations of a few days or weeks – they are far below threshold for acute effects, and small enough that they would not be expected to significantly increase lifetime fatal cancer risk.

The exposure scenario for long-duration missions into deep space is considerably different from those of short-duration missions to LEO or even to the Moon as in the Apollo era. Deep-space missions of the future are likely to be longer in duration than most if not all missions to date, with modestly shielded vehicles, and by definition will be outside the (partial) protection of LEO. In longduration mission scenarios, the dominant radiation health risks are almost certain to be those from GCRs, including a significant component of heavy ions (5). Because GCRs tend to be highly energetic, most of them pass through the moderate shielding (probably on the order of 20 g cm<sup>−</sup><sup>2</sup> ) that is to be expected on a vehicle built for crewed travel into deep space. Exposure to energetic heavy ions is unavoidable; however, shielding does attenuate the heavy ion flux due to nuclear interactions that cause the incident ions to fragment into lighter ions. Choosing shield materials to maximize nuclear fragmentation is at present the most viable strategy for reducing this exposure, though there is certainly a shielding depth at which the law of diminishing returns begins to pertain. Other approaches, including magnetic and electrostatic shielding, are not yet practical, nor is it feasible (from the cost perspective) to launch shields consisting of hundreds of gram per square centimeter of mass, or even many tens of gram per square centimeter.

In the following, we will review transport physics as it pertains to energetic charged particles encountered in space and used in radiation therapy, with particular emphasis on the unique roles played by nuclear fragmentation in these two very different settings. A brief overview of fragmentation models is also given. We will present both data and model calculations to support the conclusions outlined here, both for space radiation and for beams of interest in the clinic. It should be added that proton–nucleus collisions are also extremely important in both settings, but are not covered in detail here.

# TRANSPORT OF ENERGETIC CHARGED PARTICLES

The transport of energetic particles through spacecraft walls, equipment racks, and human tissues determines the physical dose received by astronauts in space, and the same physical mechanisms affect the beams of charged particles that are used to irradiate tumors. When charged particles traverse matter, electromagnetic interactions cause ionization energy loss, which continuously slows the incident particles, increasing their LET. These interactions are between the electromagnetic field of the projectile and the electrons surrounding the atoms in the material being traversed. The projectiles considered here are bare nuclei, fully stripped of all electrons. These interactions produce a region of relatively dense ionization along the trajectory of the projectile and can also result in the production of long-ranged, high-energy "knock-on" electrons, also known as δ-rays, which can deposit dose at a considerable distance from the main track. Detailed models of track structure (6–8) describe these complexities, which include energy deposition at significant distances from the primary track in the plane transverse to the direction of the incident particle. Electromagnetic interactions also cause Coulomb multiple scattering, but for the particles and energies of interest here, we are for the most part not concerned with this process as it produces mostly very small angle deflections. The interested reader is referred to the literature (9).

The nuclear interactions of interest span a broad range of possibilities, from highly peripheral interactions in which only a small number of nucleons are removed from the projectile to central collisions in which the incoming projectile is fragmented into a high-multiplicity spray of light ions. Also of interest in nuclear interactions is the production of target fragments, including neutrons that are capable of penetrating large depths of matter before interacting.

# Ionization Energy Loss

Ionization energy loss is a purely electromagnetic phenomenon in which a charged projectile interacts with the electrons in the atoms of the target medium. The energy lost by the projectile per unit path length is accurately described by the Bethe equation (9):

$$\frac{\text{dE}}{\text{dx}} = -\text{k}\rho \left(\frac{Z}{A}\right)\_{\text{mat}} \left(\frac{Z}{\text{\text{\textdegree\text\text\text\text\textdegree}}}\right)\_{\text{proj}}^2 \left[\log\left(\frac{2m\_e\mathbb{B}^2}{I\left(1-\mathbb{B}^2\right)}\right) - \mathbb{B}^2\right]$$

where k is a constant, *Z* refers to atomic number, *A* to mass number, β is the velocity of the moving particle relative to the speed of light, *I* is the ionization potential of the medium, and ρ its density. The subscript "mat" refers to the material being traversed (often referred to as the target, here as the shield), while "proj" refers to the projectile. The density effect, neglected in the equation above, is applicable at high energy, and additional corrections are needed at very low energies, where the curve turns over as particles approach their stopping points. The term in brackets is slowly varying with projectile energy, so that for moderate energies (β not too close to 1), dE/dx goes as (*Z*<sup>2</sup> /β<sup>2</sup> ) of the projectile, and as (*Z*/*A*) of the target material. Integrating the dE/dx vs. energy curve yields the range–energy relation for any combination of projectile and target. To a very good approximation, the proton range for a given energy and material can be scaled to obtain the range of an ion with the same velocity (or energy per nucleon) having charge *Z* and mass number *A* according to (*A*/*Z2* ). Calculations of dE/dx have been shown to be highly accurate (typically to better than 1%) over a wide range of projectiles and targets; the main uncertainties are the ionization potentials. This part of the transport problem is well understood and can be modeled with high confidence. The dependence on *Z*<sup>2</sup> and energy can be seen in **Figure 1**, which shows straightforward dE/dx vs. energy calculations for 12C ions and protons in water for kinetic energies of 10 MeV/nuc and above (the region of interest for space applications). The curves are approximately flat at high energies, but rise significantly at the lower energies that are especially relevant for hadron therapy.

# Nuclear Interactions

The electromagnetic interactions described in the preceding section are well understood from both theoretical and experimental perspectives. Nuclear interactions are also a crucial aspect of transport, but are not nearly as well understood from the theoretical perspective. Interactions between a projectile and atoms of the target are ultimately described by quantum electrodynamics (QED), the most accurate physical theory yet devised; by contrast, nuclear interactions are many-body problems that defy present-day calculational methods at the most fundamental level. That is, the particles that participate in nuclear interactions are themselves composites (nuclei contain nucleons, and nucleons contain quarks and gluons), and the fundamental theory that describes these interactions is quantum chromodynamics (QCD), which is only tractable in the limit of interactions with large momentum transfers. QCD has not yet been successfully applied to nucleus–nucleus collisions at the energies of interest here. The lack of a fundamental theory has led to the development of many semi-empirical models to describe nucleus–nucleus interactions, and considerable effort continues to be put into development of these models and benchmarking them (10) against the limited set of pertinent data that are available (2).

Outgoing particles from a heavy-ion fragmentation reaction are typically described as either "projectile" fragments or "target" fragments. Projectile fragments approximately preserve the direction and velocity of the incident particle. Target fragments are produced when the nuclei in the medium being traversed participate in an interaction, and they or their remnants are left in an excited state. These states decay via emission of nucleons, including neutrons. Target fragments are emitted more or less isotropically in the laboratory frame, and have relatively low energies, on the order of tens of MeV or less. A nucleus–nucleus collision can, if it is central (i.e., head-on), produce a large multiplicity of projectile fragments, each of which has lower LET than did the incident ion, owing to the fact that dE/dx goes roughly as (*Z/*β)2 , and here β is roughly constant while *Z* decreases. The sum of the LETs of the projectile fragments is always less than the LET of the primary ion. Charged target fragments can have very high LETs, but have very short ranges. The typical target-fragment energy range is also the range in which the radiation weighting factor for neutrons is highest. Neutrons can also be produced as projectile fragments, stripped from the projectile.

# Nuclear Cross Sections and Bragg Curves

Cross sections for nucleus–nucleus interactions that produce a charge change in the projectile are accurately described by a simple energy-independent model of overlapping spheres, as first postulated by Bradt and Peters (11). Wilson and Townsend (12) presented a slightly modified version for use in NASA space radiation transport codes:

$$\sigma\_{\rm cc} = \pi r\_0^2 \left( A\_{\rm proj}^{1/3} + A\_{\rm aug}^{1/3} - 0.2 - 1 / A\_{\rm proj} - 1 / A\_{\rm aug} \right)^2$$

where σ*cc* is the charge-changing cross section, the *A* values refer to the mass numbers of the projectile and target, and *r*0 is the nucleon radius, which is known from other data to be roughly 1.2–1.5 fm. Several other variations on the basic Bradt–Peters model exist (13, 14), but all yield similar results. As will be discussed below, the Wilson–Townsend formula reproduces measured chargechanging cross sections over a wide range of projectile and target masses, for energies from a few hundred MeV/nuc to at least 1 GeV/nuc. We can use data to constrain *r*0 and also to investigate the "nuclear transparency" term in the above formula, which is represented by a constant with value −0.2. This term corresponds to the probability that the spheres overlap without causing the projectile to lose charge; representing this probability by a simple constant may be an oversimplification.

Measured Bragg curves obtained with monoenergetic ion beams illustrate the competing effects of fragmentation and ionization energy loss. **Figure 2** shows depth-dose curves obtained for three different beams at the NASA Space Radiation Laboratory (NSRL) (15). The NSRL is a dedicated NASA facility at the Brookhaven National Laboratory. The Bragg curve data are publicly available on the NSRL web site. High-density polyethylene (CH2, with density ρ = 0.97 g cm<sup>−</sup><sup>3</sup> ) was used as a moderator and parallel-plate ionization chambers were used to record the relative ionization before and after the moderator; the ratio of the two (after to before) is plotted on the *y*-axis. The shortestrange beam of the three considered here is the 200 MeV/nuc 12C, which penetrates to a depth of about 8.4 cm of the target material before stopping. The Bragg curve increases relatively quickly with increasing target depth due to the low energy of the primary beam ions; this case is dominated by energy loss. At 293 MeV/nuc, ions of the same species travel nearly twice as far compared to the 200 MeV/nuc ions, and the Bragg curve shows a slower rise and a smaller peak. This is because the initial dE/dx is lower at the higher energy, and also because fragmentation of the primary beam ions begins to exert a significant influence. Using published data (16), we estimate that 12C ions in polyethylene of this density

have an interaction mean free path of about 23 cm. The fraction of surviving primaries at depth *x* is given by *e*<sup>−</sup>x/<sup>λ</sup> where λ is the interaction mean free path (mfp), so that over the first 12 cm of the target, some 40% of them undergo a charge-changing interaction, and at the Bragg peak (16 cm), roughly 50% of them have fragmented. About 20% of these interactions produce boron fragments (*Z* = 5), which have slightly longer ranges than the carbon primaries, and somewhat lower LET. These contribute to the distal edge just past the Bragg peak, while lighter fragmentation products – dominantly 4 He ions – give a non-negligible dose for several centimeter beyond the Bragg peak. The distal edge dose is also apparent for 200 MeV/nuc 12C, but is not nearly as prominent because a smaller fraction of primary ions undergo fragmentation before reaching the Bragg peak.

The Bragg curve for 600 MeV/nuc 16O is also shown in **Figure 2**, primarily to show a contrasting case in which fragmentation dominates over ionization energy loss. For this beam, dE/dx is initially relatively low and (compared to the lower-energy beams) in a relatively flat portion of the dE/dx curve. The Bragg peak, therefore, occurs deep in the target, at about 37 cm. Again using published data, the mfp for 16O to undergo a charge-changing interaction in CH2 of this density is found to be about 17 cm, so that the survival fraction of primaries at the ionization peak is only 11%. The remaining mix of particles has comparatively low LET, so that the peak ionization barely surpasses the initial value at the entrance. Over most of the target depth, the 600 MeV/nuc 16O beam produces ionization ratios <1, that is, less than that of the initial, unfragmented beam. We will return to the subject of these Bragg curves in the discussion of fragmentation models below.

### Projectile Fragments

Projectile fragments retain, to a large degree, the velocity and direction of the projectile, which makes intuitive sense considering that they are essentially intact pieces of the incident nucleus. However, velocities and directions are not exactly preserved, and the deviations are especially important in the clinical setting where these changes may contribute to dose outside the treatment volume. The changes of momentum of projectile fragments compared to the primary are mostly well-described by the statistical theory of Goldhaber (17). Projectile fragments in general have shifts in both transverse and longitudinal momentum; the change in each Cartesian coordinate is normally distributed, i.e., the probability distribution goes as exp(−*p*<sup>2</sup> /2σ<sup>2</sup> ) where σ = σ <sup>2</sup> 0 2 *A A A A* 1 frag proj frag proj ( ) − /( ) − and σ0 is on the order of 90 MeV/c. Goldhaber's work elegantly derives these relationships in two independent ways: from considerations of the Fermi motion of the nucleons inside the projectile nucleus prior to the collision, and also from thermal equilibrium, with σ0 directly related to the equilibrium temperature. The theory was developed to explain the momentum distributions measured in nuclear emulsion by Heckman et al. (18), and has been validated with more recent data (19–21) using an indirect method. In the latter work, σ0 was tuned to match individual data sets, and the model was then used to make essential corrections for angular acceptance, enabling extraction of light-fragment production cross sections from measurements made at 0° with small-acceptance detectors. These cross sections probe central (i.e., head-on) collisions, whereas the more common peripheral interactions tend to produce fragments with a small charge change from the primary.

As previously mentioned, in the clinical setting, fragmentation reactions lead to undesirable results, because fragments do not necessarily deposit their energy in the treatment volume. A qualitative assessment can be made using the formulas above. Given a 12C projectile and (as is commonly produced) a 4 He fragment, the width of the momentum distribution in one transverse dimension is about 38 MeV/c, and in the two transverse dimensions is 54 MeV/c. If an interaction occurs near the entrance, when the primary has a kinetic energy of, for example, 250 MeV/nuc, then the longitudinal momentum of the fragment is roughly 3 GeV/c, so that the distribution of the polar angle has a width of about 1°. Since the distribution is normal, 95% will be contained within a cone of 2° width, 99.7% within 3°, etc. If the distance between the interaction point and the nominal stopping point of the primary is 50 mm, then deflections of 2° or greater produce transverse offsets of 1.7 mm or greater. For particles starting in the center of the beam, fragments undergoing such small deflections may remain within the treatment volume, but some particles starting near the edge of the beam will produce fragments that deposit energy outside the desired volume. This behavior is readily modeled, as is Coulomb scattering, as described below. Fragmentation can be thought of as creating a halo of projectile fragments that will tend to smear out what would otherwise be a sharp lateral edge defined by the beam.

The fragmentation of 12C into helium produces dose in the far distal edge of the Bragg curve. A reasonably accurate estimate of this effect can be deduced from elementary considerations (22). Closer to the Bragg peak, other fragment species contribute, but hydrogen and helium are the only ions that can penetrate far past the Bragg peak.

### Target Fragments

Empirical understanding of the composition of GCRs and of nuclear fragmentation owes much to work done with nuclear emulsions flown to high altitudes in the late 1940s and 1950s (23). Using a visual detection medium allows for the observation of short-ranged, high-LET target fragments emerging from interaction vertices, sometimes referred to as "stars." An example of an interaction vertex is shown in **Figure 3**, in which a 130 MeV/ nuc 28Si beam ion (incident from the left) interacts with a heavy nucleus in the emulsion. These fragments are difficult to detect by other means, but they are important in that they produce very large, localized energy depositions in the vicinity of the interaction point. Both charged fragments and neutral particles (which, unlike the charged fragments, may penetrate long distances) can emerge from the remnants of the struck nucleus, which may in the immediate aftermath of the collision be in an excited state, from which it decays to a ground state via particle emission. Target fragments are emitted isotropically in the rest frame of the target, which to a good approximation is also the laboratory frame. In addition to the local energy depositions from charged fragments, the production of neutrons may be dosimetrically important, as their subsequent interactions can produce additional high-LET secondaries. In the context of radiation therapy, these may occur

1The photomicrograph used in Figure 3 was made available by P. Zarubin et al. It, and many others, are available online at http://becquerel.jinr.ru/movies/movies.html

outside the tumor volume; in the context of space radiation, target-fragment neutrons produced in spacecraft walls can reach inhabited areas and contribute to crew exposures.

# High Level Overview of Models

Monte Carlo codes, such as GEANT4 (24), MCNPX (25), FLUKA (26), and PHITS (27), have been developed by the high-energy and nuclear physics communities to model the transport of ions through matter. In the space radiation protection community, the same codes are used, along with an analytic transport model known as HZETRN that was developed within NASA by Wilson et al. (28) and subsequently extended (29). In the Monte Carlo codes, particles are followed in small steps through the medium, and the relevant physical processes (ionization energy loss, Coulomb scattering, and, for ions, nuclear interactions) are simulated in each step. The analytic approach, based on numerical solution of the Boltzmann equation, yields faster computation times in some cases, but many approximations are required, and these may compromise the accuracy of the results. For some purposes, such as spacecraft design, high accuracy is not needed in the initial stages and analytic calculations may suffice, but this approach is not applicable to treatment planning. Monte Carlo codes generally require considerable effort to define the geometry of the target (e.g., a large detector, a spacecraft, or a human in a therapy beam), and may require relatively long run times depending on the complexity of the geometry.

For either space radiation transport or treatment planning in a heavy ion beam, a nuclear physics model is needed, regardless of whether the analytic or Monte Carlo approach is used. The diversity of models likely accounts for the differences observed between codes (10, 30). In some of the Monte Carlo codes, there are also a variety of options available, i.e., the user selects a particular nuclear interaction model or models. Unlike HZETRN, the Monte Carlo codes do transport calculations in three dimensions, and are inherently capable of capturing important details of nuclear reactions that are lost in one-dimensional transport.

In the following sections, we use the PHITS Monte Carlo code to illustrate the important effects of shielding in modifying GCR fields (see Nuclear Interactions and Shielding in Space) and to compare calculated Bragg curves to the NSRL Bragg curve data (see Nuclear Interactions of Carbon Beams). These comparisons allow us to demonstrate some of the important capabilities of Monte Carlo codes vis-a-vis heavy ion transport, at least in relatively simple beamline geometry. This is not intended to constitute an endorsement of PHITS, but rather reflects our previous use of the code in similar geometries. Though the goal of reproducing Bragg curves may seem straightforward, it is in fact challenging to model the experimental results with high precision. And while not all aspects are perfectly reproduced, the relatively good agreement with the data gives us confidence that the model represents the mixtures of primaries and fragments that are present before, in, and beyond the Bragg peaks, providing insights that are not available from the data alone. It is highly likely that similar results would be obtained using the other Monte Carlo codes mentioned above.

# NUCLEAR INTERACTIONS AND SHIELDING IN SPACE

In space, protons and high-charged nuclei undergo nuclear interactions as they traverse the hull of a spacecraft and the equipment inside. These are the same types of interactions that occur in the treatment setting as particle beams traverse healthy tissues on the way to the target volume. Nuclear interactions may produce a large number of secondary particles, particularly when incident energies are large. Shielding generally reduces the hazard from heavy ions due to the effects of nuclear fragmentation. Although heavy ions (those with charge Z > 2) represent only about 1% of the GCR flux, their contribution to dose in unshielded space can be 30 to 40% of the total. This disproportionate contribution can be understood by recalling that energy loss (which is directly related to dose imparted) is proportional to *Z2* , that is, to the square of the projectile's charge. The dose-weighted average charge of GCR heavy ions is about 10, so that the dose per particle is roughly 100 times greater than that of a proton having the same kinetic energy per nucleon. The contributions of GCR heavy ions to dose equivalent are even larger than their contributions to dose, owing to the large factors by which their fluxes are weighted. In free space, iron ions (*Z* = 26 and average LET about 155 keV/μm in water) make the largest contribution of any single ion species, despite being less abundant than protons by nearly four orders of magnitude.

Given that spacecraft to date have been constructed with aluminum hulls, and given our knowledge of the fragmentation cross sections of many ion species at typical GCR energies, we can estimate how much the fluxes of various primary ions are attenuated by fragmentation before passing through a hull. **Table 1** shows the results for several important species using cross sections calculated with the Townsend and Wilson energyindependent formula given above. Note that for the lighter ions, we expect there to be some replenishment by fragmentation of heavier ions (e.g., Fe + Al → Si + X, etc.); this is discussed further in Section "Measurements and Calculations for Space" below. There is also attenuation due to ionization energy loss, particularly at the larger depths, as will also be shown below. It is notable that 20 g cm<sup>−</sup><sup>2</sup> of aluminum is sufficient to break up the majority of incident iron ions and roughly half of magnesium and silicon ions.

# The Role of Fragmentation in Space Radiation Protection

As the preceding has shown, fragmentation of primary GCR heavy ions as they traverse the hull of a spacecraft strongly influences the radiation environment inside. The flux of heavy ions is reduced behind shielding, which may result in a reduction in dose and certainly results in a reduction in dose equivalent. Because much of the uncertainty in the biological response to space radiation is due to uncertainty in response to heavy ions, the reduced flux of these ions behind shielding may also reduce some of the uncertainty in risk estimation.

It follows from the above considerations that an effective shield against GCRs is one that efficiently breaks up heavy incident ions into lighter ions. Put another way, we would expect materials with the largest cross sections per unit mass to be the best shields against GCRs. An important calculation verifying this was carried out by Wilson et al. (31), who found that a pure hydrogen shield would be extremely effective at reducing the dose equivalent from GCRs, and that the performance of other materials worsens with increasing atomic number. These calculations inspired subsequent experimental work (32, 33)

TABLE 1 | Calculated attenuation of high-energy ions by fragmentation in aluminum using geometric cross sections.

that confirms the effectiveness of hydrogen in fragmenting heavy ions. It has subsequently been pointed out that the reductions of dose and dose equivalent at a point surrounded by hydrogenous shielding materials may be largely offset by the further transport of the components of the radiation field into a human body. That is, the fragmentation products of both proton–nucleus and nucleus–nucleus collisions, which include neutrons and lowenergy protons, deposit doses of high-LET radiation inside the body that may be comparable to those from unattenuated GCR heavy ions, in terms of biological effect.

Despite these complications, point measurements and calculations of dose and dose equivalent are still important for characterizing the radiation environment to which crew members are exposed. In particular the effects of fragmentation can be assessed in terms of the average radiation quality of the field at a particular point behind shielding. In the methodology prescribed by ICRP 60, the average quality factor is given by < *Q* > = H/D, where *H* is the dose equivalent and *D* the dose. The dose and dose equivalent are given by

$$D = \frac{1}{\rho} \int \frac{d\Phi}{dL} L \text{d}L \text{ and } H = \frac{1}{\rho} \int \frac{d\Phi}{dL} \text{LQ}(L) \text{d}L$$

where dΦ/dL is the differential fluence and the quality factor *Q* is solely a function of the LET, *L*, and ρ is the density of the target material in units of g cm<sup>−</sup><sup>3</sup> . NASA has revised the ICRP 60 quality factors (34) with separate factors for solid tumors and leukemia. The NASA quality factors depend on the effective charge and velocity of the ion according to (Z\*2/β<sup>2</sup> ), rather than LET, a change intended to represent track structure. However, for ease of calculations, and making use of our existing analysis tools, we use the more familiar ICRP 60 *Q*(*L*) in the following. It is also notable that, subsequent to the publication of the revised NASA quality factors, analysis by Borak et al. (35) showed that the (*Z*\*2/β<sup>2</sup> ) dependences could be re-cast as LET dependences with only minor differences in the results for several space environment scenarios. The study was motivated by practical concerns about the difficulties of accurately measuring ion velocities at relativistic speeds using compact space-borne detectors.

As mentioned above, in free space, < *Q* > takes on values between 6 and 7, depending on the phase of the solar cycle. Considering that roughly 99% of GCRs are hydrogen or helium nuclei with *Q* = 1, this relatively large average value is remarkable. However, as will be shown in the next section, < *Q* > can be somewhat reduced by moderate depths of shielding.

# Measurements and Calculations for Space

A large body of experimental data has been obtained in LEO, using detectors flown on the Mir Station, Space Shuttle, and the International Space Station (ISS). Historically, many of the measurements have been made using passive detectors, which integrate over all contributions. In the case of LEO, this means passive detectors record a < *Q* > value that is the dose-averaged combination of the GCR and trapped radiation. This does not provide sufficient information to assess the effect of shielding on GCR < *Q* > values. For that, we must use data from active detectors, such as DOSTEL (36, 37), that have time resolution and which, therefore, allow for separate < *Q* > measurements for GCR and trapped particles. Recent DOSTEL measurements from ISS indicate a GCR < *Q* > in the vicinity of 3.1 in the Columbus module. This is quite comparable to results obtained by the Radiation Assessment Detector (RAD) detector (38), which measured a < *Q* > of 3.82 ± 0.25 during the transit for Earth to Mars in 2011–2012 (39) inside the modestly shielded Mars Science Laboratory spacecraft, and a value of 3.05 ± 0.30 on the surface of Mars (40) under somewhat more shielded conditions. Because the dose rate is far less affected by shielding than is dose equivalent (owing mainly to the production of secondary radiation in the shield), the reduction in < *Q* > is the main benefit of shielding.

Simple model calculations performed with PHITS give us some insight into the important characteristics of the GCR radiation field behind 20 g cm<sup>−</sup><sup>2</sup> of aluminum, which might be a typical shield for a human-crewed vehicle going into deep space. In this example, the GCR was treated as a pencil beam and shot at an aluminum target of the desired depth (7.4 cm). Particles crossing a cylindrical void downstream of the target were scored; the scoring region was 10 cm in diameter, large enough to contain the vast majority of particles emerging in the forward direction from the target. The void was separated from the downstream edge of the target by 1 mm of air, which stops extremely low-energy particles exiting the target. Although the simulated beam geometry, with a small parallel beam and a large detector, is not a realistic representation of the space environment, the scoring region used was large enough to capture the vast majority of particles exiting the target. This was tested with a simulated aluminum target 20 g cm<sup>−</sup><sup>2</sup> in depth; it was found that increasing the lateral dimensions of both the target and scoring regions by factors of two (a factor if 4 increase in areas) increased the number of scored charged particles by 3.3%. A total of 5 × 105 simulated events were run, sufficient to make statistical errors negligible in the analysis. For computing dosimetric quantities, only particles with at least 10 keV/nuc of kinetic energy were scored. (This cut excluded <0.1% of neutrons and about 0.05% of charged particles.)

Initial charge and energy distributions were based on the Badhwar–O'Neill GCR flux model (41), for a solar modulation potential corresponding roughly to average conditions in 2014 and 2015, the most recent (weak) solar maximum. The GCR energy spectrum is harder at solar maximum than at solar minimum, i.e., relatively fewer low-energy ions are present due to the shielding effect of the interplanetary magnetic field. We begin the discussion by re-examining an aspect mentioned above, the

re-population of ion species by "feed-down" from fragmentation of heavier ions. **Table 2** shows, for the same ion species shown in **Table 1**, the expected losses due solely to fragmentation (based on energy-independent cross sections as per **Table 1**) and the predicted total attenuation of particle of that species, integrated over all incident energies using a more complete representation implemented in PHITS. The increased attenuation losses compared to those from fragmentation alone come about because some of the lower-energy GCR ions lose all their energy via ionization and come to rest in the shield. The picture of attenuation changes considerably when we consider only high-energy ions, as in the far-right column of **Table 2**. When incident ions with energies below 700 MeV/nuc are excluded (because many of them stop in 20 g cm<sup>−</sup><sup>2</sup> of aluminum), the number of carbon ions found after the target (counting ions of all energies) is actually greater than the number of incident by about 2%. This is due to feed-down from heavier species. There is a weaker, but not negligible, effect for the higher-*Z* GCRs, e.g., high-energy oxygen ions are only about one-third as depleted as would be expected simply based on fragmentation losses, etc. The results in **Table 2** also include the (presumably small) effects of energy dependence in the nuclear cross sections.

# Effects of Fragmentation on Dose and Dose Equivalent

Because a large proportion of GCRs have high energy, they are capable of producing large multiplicities of secondary particles as they traverse a spacecraft hull. These secondary particles are generally lower in LET than the primaries that created them. The net result tends to be (depending somewhat on the shield material and its depth) that dose is only slightly changed by the shield, but dose equivalent may be reduced significantly through the reduction in < *Q* >. **Table 3** shows some results from the simulation described above, with a narrow beam of 106 GCR-like ions incident on a 20 g cm<sup>−</sup><sup>2</sup> aluminum target.

The fractional change in dose from charged particles is simply the ratio of the *N* × <*L*> products, which works out to about a 12% decrease. There is an additional contribution to dose and dose equivalent from neutrons. In this example, we estimated the neutron contributions using conversion factors given in ICRP Publication 74 (42), in broad energy bins. The yield of neutrons is large, about 0.5 per incident GCR ion, making the statistical errors in the following quite small. Both dose and dose equivalent contributions of neutrons are on the order of 2% of the totals, so that the overall decrease in dose is roughly 10%. The dose equivalent from all particles behind the target is reduced from the incident dose equivalent by nearly 50%, driven mainly by the

change in < *Q* >. Interestingly, the value of < *Q* > found in this simulation is very close to the value of 3.8 found during the Mars transit measurement made by MSL-RAD, which was under highly inhomogeneous shielding that averaged roughly 20 g cm<sup>−</sup><sup>2</sup> . The shielding in that instance was a mix of materials, including tanks of hydrazine fuel that powered MSL's descent vehicle.

The PHITS results were checked against the HZETRN code as implemented in the NASA OLTARIS tool (43). HZETRN predicts about a 40% reduction for this depth of aluminum compared to the 50% reduction predicted by PHITS. Dose results showed a qualitatively similar trend, as OLTARIS predicts a 10% increase in dose behind the target. Lastly, OLTARIS predicts a < *Q* > of 3.5 behind the shield, indicating that the bulk of the disagreement is likely to arise in the simulated multiplicities of low-LET particles, of which OLTARIS predicts a greater number. These drive up dose and to a lesser extent dose equivalent, while driving < *Q* > to a lower value. The larger dose but smaller < *Q* > result in nearly equal dose equivalent estimates from the two models.

These results are, in principle, dependent on the GCR flux model used. Even with a given model, results will vary as a function of the solar modulation specified for the calculation. An additional important caveat to the results above is that the simulations lacked a "back wall." That is, the target is followed by the scoring volume, with nothing additional downstream. If a second wall is added (a geometry significantly more like a spacecraft or surface habitat), the effects of neutrons and other particles backscattered from the back wall appear to be significant (44).

# NUCLEAR INTERACTIONS OF CARBON BEAMS

The effects of nuclear fragmentation that were elucidated in the discussion of space radiation shielding are, of course, also at work in heavy-ion radiotherapy. Fragmentation of heavy ions reduces < *Q* > at points behind modest depths of shielding in space, and this is generally desirable. It is, however, an undesirable effect in treatment, where one would like to have the highest possible biological effectiveness at the treatment site. Furthermore, as the above discussion highlighted, hydrogen is uniquely effective in terms of the fragmentation it causes per unit mass, and while this may eventually lead to the use and/or development of hydrogenous shields for space, it means that the high hydrogen content of healthy tissues in the entrance region efficiently fragments treatment beams.

# Carbon Beam Bragg Curves

The Bragg curves shown above for 200 and 293 MeV/nuc 12C were simulated, again using PHITS. In these simulations, the beamline geometry has a better correspondence to the treatment situation than does the simulation in which the GCR was treated as a pencil beam. It should be borne in mind that actual treatment planning makes use of spread-out Bragg peaks in order to treat finite tumor volumes. Furthermore, the simulations performed here did not represent the NSRL beamline in great detail. On the real beamline, the incident beam enters through a thin window, traverses an air gap, and enters the first ionization chamber. All ionization chambers have thin but finite entrance and exit windows, as well as foils that are not represented in the simulation, nor are the air gaps. Finally, the beam energy is not known precisely, and is actually inferred from the Bragg curve measurement. The fidelity of the simulation is, therefore, not perfect. Nonetheless, interesting trends are observed, as can be seen starting with **Figure 4**, which shows measured and simulated ionization ratios as a function of polyethylene target depth.

Agreement over the first 7 cm is excellent, but slight deviations begin to appear beyond that point, as the surviving carbon ions and heaviest fragments slow down and approach the ends of their ranges. The peak ratio in the simulation occurs slightly before that in the data (8.06 g cm<sup>−</sup><sup>2</sup> in the simulation, 8.13 g cm<sup>−</sup><sup>2</sup> in the

data), and has a higher value (8.3 vs. 6.5). The discrepancies are more visible in **Figure 5**, which zooms in on the peak region. The distal edge appears to be less populated in the simulation than in the data, which is consistent with the simulation slightly underestimating the probability of fragmentation as the carbon ions traverse the target. If the model had a higher nuclear cross section, it would both reduce the peak value of the ionization ratio and increase the population of fragments in the distal edge.

The location of the simulated peak is slightly offset from the peak location in the data, by <1%. This could easily be an artifact of the inaccuracies of the simulated beamline, and/or a slight difference in beam energy between the nominal 200 MeV/nuc and the actual energy. If the difference between the measurement and simulation is attributable only (or dominantly) to the initial energy, the required extra range would be fully accounted for if the beam energy was 200.5 MeV/nuc, and in fact the NSRL team estimates the beam energy to have been 200.2 MeV/nuc (though 200.0 MeV/nuc was used in the simulation).

Finally, in **Figure 6**, we show data and simulations in a 4-cm region of the Bragg peak region for the 293 MeV/nuc 12C beam. The differences between the data and simulation are qualitatively the same at this energy as at the lower energy: the peak is again slightly shifted to a smaller depth in the simulation (15.37 vs. 15.95 g cm<sup>−</sup><sup>2</sup> ) and again has a higher peak value in the simulation (5.43 vs. 4.77). The higher peak values in the simulation vs. data for both 12C energies are likely due to having simulated a perfectly monoenergetic incident beam, whereas the real beam has a finite momentum spread due to the optics of the beamline transport system.

The distal edge, which is populated mostly by hydrogen and helium ions (including a significant share of 2 H), falls off much more rapidly in the simulation than in the data. It is possible that the differences in the distal edge could be due to the limited radius of the cylindrical volume used in the simulation to score particles exiting the target, which was set to 10 cm, far wider than the pencil beam diameter (1 cm). Some of the simulated exiting particles were likely more than 10 cm from the beam axis and, hence, were not scored, whereas the actual ionization chambers that were used to obtain the data are much wider.

Our broader purpose here is not to diagnose possible shortcomings in the model or the beamline, but rather to show that even with a fairly crude simulation of the beamline, fragmentation and energy loss effects can be modeled with good fidelity for a therapy beam. The simulations also give insight into the composition of particles in the rising edge, Bragg peak, and distal edge of the beam. The simulations indicate that there are roughly equal numbers of H and He ions in the distal edge, of which the He ions contribute approximately 80% of the dose. In the peak region, about 45% of the charged ions are carbon ions that survive traversal through nearly 16 g cm<sup>−</sup><sup>2</sup> , well in line with the 50% estimate given above, especially since here the total count of particles includes fragments that are generally produced with multiplicities >1. The remaining particles consist of about one-third helium ions, 10% hydrogen ions, 7% boron, with the remainder divided more or less equally between lithium and beryllium. When higher-energy beams are used in treatment, the fraction of carbon ions in the Bragg peak region is even lower than this.

## Geometric Cross Sections

A fairly large collection of nuclear cross section data was obtained in our previous experiments. Most but not all results have been published (16, 19–21). Projectiles included 4 He, 10B, 12C, 14N, 16O, 20Ne, 24Mg, 28Si, 40Ar, 48Ti, and 56Fe. Target data for H, C, Al, Cu, Sn, and Pb were obtained. Beam energies ranged from 230 to 1200 MeV/nuc, a range in which the approximation of energyindependent cross sections appears to be valid for targets other than H. Data were obtained for both total charge-changing cross sections and fragment production cross sections with no isotopic resolution. Here, we look at the measured charge-changing cross sections in comparison with the Wilson–Townsend formula given above, treating the nuclear radius (nominally 1.26 fm) and the transparency term (nominally 0.2) as adjustable parameters. A series of χ<sup>2</sup> values was calculated for agreement between the data and model, and is shown as a contour plot in **Figure 7** where the color indicates the level of agreement. Though the uncertainties on the charge-changing cross sections are typically on the order of ±3 to 5%, we have inflated them here to ±10% to obtain reasonable χ<sup>2</sup> values on the order of 1 per degree of freedom for the best fits. Clearly, the strong correlation between parameters yields relatively poor constraints. Equally good combinations occur in the range from 1.25 to 1.30 fm with transparency terms varying from 0.2 to 0.4 depending on the nuclear radius value.

For all parameter variations tried here, the majority of the χ<sup>2</sup> comes from data taken with the lighter targets (H, C, Al), while the agreement is substantially better with the heavier targets (Cu, Sn, Pb). If the search for minimum χ<sup>2</sup> is limited to just the light targets, the best-fit parameters are 1.235 fm for the nuclear radius and 0.16 for the transparency term.

A qualitatively similar analysis effort was undertaken by Heckman et al. (45) using nuclear emulsion data, with fits to the most basic form of the Bradt–Peters geometric cross section model. Across a range of projectile/target masses, a consistent

value of the nuclear radius, *r0*, was found (1.36 ± 0.02 fm), but a highly variable value of *b* was needed to fit the data. Of particular interest, for 4 He projectiles, a very large *b* of 1.10 ± 0.04 was found, indicating fragmentation cross sections smaller than expected from the geometry of heavier ions. A likely explanation is the tight binding of the nucleons in 4 He, so that these ions are less likely than others to break up when undergoing peripheral collisions. In view of the deleterious effects of fragmentation in the treatment setting, this seems to suggest that 4 He might be a particularly good ion to use in therapy. The measured chargechanging cross sections on H and C show that the mfp of 4 He in polyethylene is 66 g cm<sup>−</sup><sup>2</sup> , so that at a penetration depth of 16 g cm<sup>−</sup><sup>2</sup> (the Bragg peak location of the 290 MeV/nuc 12C beam), some 78% of the 4 He is still intact, compared to about 50% for 12C. The corresponding energy for 4 He to stop at the same depth is about 155 MeV/nuc. Because of the difference in charge (2 vs. 6), the peak ionization ratio would be expected to be lower than the value of about 5 found for 12C; a PHITS simulation suggests that the peak value would be between 4 and 5. This may be a worthwhile tradeoff given that the lateral and distal doses would be significantly less than they are with carbon beams.

# CONCLUSION

Nuclear fragmentation is an important phenomenon both in space radiation protection, where it reduces exposure to heavy ions with high biological effectiveness, and in heavy-ion therapy where it dilutes the effectiveness of the primary beam ion and causes dose to be deposited outside the treatment volume. Previous code comparisons, along with the simulations and comparisons to beam and flight data shown here, give us confidence that current Monte Carlo codes are able to predict the combined effects of fragmentation and energy loss both in space and in carbon ion therapy with good fidelity. The small fragmentation cross section of 4 He suggests that it may be a particularly useful ion for therapy.

# AUTHOR CONTRIBUTIONS

CZ did the majority of writing and the transport model calculations used in the paper. CT provided the NSRL experimental data and did a significant share of the writing, and proofread and corrected the parts written by CZ. The basic idea for the article grew out of discussions between the two authors about the pitfalls of carbon ion therapy and the quest to find the optimal treatment ion species for radiation therapy.

# ACKNOWLEDGMENTS

We thank Drs. A. Rusek and M. Sivertz of Brookhaven National Laboratory for making the Bragg curve measurements at NSRL and for making the data publicly available. We thank Dr. P. Zarubin of the Joint Institute for Nuclear Research for the use of the emulsion photomicrograph used in **Figure 3**, and for valuable discussions. This work was supported at Lockheed Martin by the NASA Health and Human Performance Contract NNJ15HK11B, and at the Brookhaven National Laboratory under NASA contract NNJ07HE781 and the U.S. Department of Energy contract DE-AC-2-98CH10886.

# REFERENCES

45. Heckman HH, Greiner DE, Lindstrom PJ, Shwe H. Fragmentation of 4He, 12C, 14N, and 16O nuclei in nuclear emulsion at 2.1 GeV/nucleon. *Phys Rev C* (1978) **17**:1735–47. doi:10.1103/PhysRevC.17.1735

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2016 Zeitlin and La Tessa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*


**6. Autosomal dominant polycystic kidney disease (Potter type III)**

Definition: ADPKD is a bilateral renal anomaly where cysts arise from all areas of the nephron or collecting ducts. It commonly appears in adults but can rarely be seen prenatally, especially when screening is targeted to families at risk.

Clinical facts:

• Risk of chromosomal anomalies (5–10%).

drome, and tuberous sclerosis.

• Perform careful follow-up.

**8. Pelvis dilatation**

• 3 mm in the first trimester.

• 7 mm after 32 weeks.

obstruction.

• 4 mm between 14 and 22 weeks. • 5 mm between 22 and 32 weeks.

• Above 10 mm always pathology.

Incidence: 1–5:500 newborns.

trimester.

• Risk of nonchromosomal syndromes may be found in VACTERL, cerebro-reno-digital syn-

Renal Anomalies

281

http://dx.doi.org/10.5772/intechopen.71925

Definition: the dilatation of the pelvis is the most common anomaly detected by ultrasound. It can present as a mild pelviectasis or as hydronephrosis. Though numbers may vary in dif-

• Mild pelviectasis [2]: above 4 mm in the second trimester and above 7 mm in the third

• Hydronephrosis [4]: above 7 mm between 16 and 20 weeks and above 10 mm after 20 weeks.

Pathology: mild pelviectasis has been associated with aneuploidy (minor marker), especially trisomy 21. The mechanism for unilateral hydronephrosis may be obstruction of the ureteropelvic junction, vesicoureteral reflux, and obstruction of the vesicourethral junction. Bilateral hydronephrosis may be caused by bilateral vesicoureteral reflux or by urethral

Ultrasound findings: renal scanning reveals a dilated renal pelvis above the cutoff for the respective gestational age. Frequently, when hydronephrosis is installed, the calyces are also

• Look for renal cysts when urinary tract obstruction is diagnosed.

• Bilateral: oligoamnios + distended bladder + bilateral renal cysts.

• Amniocentesis is indicated when associated anomalies are present.

• Unilateral: renal cysts + hydronephrosis/hydroureter.

• May be impossible to differentiate from MCDK. • Termination should be offered for bilateral form.

ferent sources, generally values are around these figures:

Limits of normal size for gestational age have also been described [2]:

Incidence: 1:1000.

Pathology: the genetic mechanism involves two genes PKD1 and PKD2 on chromosome 16. The condition is associated with multiple renal cysts, hypertension, and renal failure. Cysts are also present in the liver, spleen, and pancreas.

Ultrasound findings: the kidneys are hyperechoic, in some cases only in the cortical region. Amniotic fluid and the bladder are usually normal.

Differential diagnosis: ARPKD (autosomal recessive polycystic kidney disease). Normal fluid, bladder, and family history help us make the difference.

Clinical facts: